Imidazole compounds for the treatment of neurodegenerative disorders

ABSTRACT

The present invention relates to compounds of the Formula I  
                 
 
wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 7  and A are as defined. Compounds of the Formula I have activity inhibiting production of Aβ-peptide. The invention also relates to pharmaceutical compositions and methods for treating diseases and disorders, for example, neurodegenerative and/or neurological disorders, e.g., Alzheimer&#39;s disease, in a mammal comprising compounds of the Formula I.

CROSS REFERENCE TO RELATED APPLICATION

The present application claims benefit of U.S. Ser. No. 60/555,623 filedon Mar. 23, 2004, which is incorporated by reference herein in itsentirety.

FIELD OF THE INVENTION

The present invention relates to the treatment of neurodegenerativeand/or neurological disorders, such as Alzheimer's disease, in mammals,including humans. This invention also relates to inhibiting, in mammals,including humans, the production of Aβ-peptides that can contribute tothe formation of neurological deposits of amyloid protein. Moreparticularly, this invention relates to imidazole compounds,pharmaceutical compositions comprising such compounds and methods ofusing such compounds, i.e., for the treatment of neurodegenerativeand/or neurological disorders, such as Alzheimer's disease, related toAβ-peptide production.

BACKGROUND OF THE INVENTION

Dementia results from a wide variety of distinctive pathologicalprocesses. The most common pathological processes causing dementia areAlzheimer's disease (AD), cerebral amyloid angiopathy (CAA) andprion-mediated diseases. AD affects nearly half of all people past theage of 85, the most rapidly growing portion of the United Statespopulation. As such, the number of AD patients in the United States isexpected to increase from about 4 million to about 14 million by themiddle of the next century.

Treatment of AD typically is the support provided by a family member inattendance. Stimulated memory exercises on a regular basis have beenshown to slow, but not stop, memory loss. A few drugs, for exampleAricept™, provide treatment of AD.

A hallmark of AD is the accumulation in the brain of extracellularinsoluble deposits called amyloid plaques and abnormal lesions withinneuronal cells called neurofibrillary tangles. Increased plaqueformation is associated with an increased risk of AD. Indeed, thepresence of amyloid plaques, together with neurofibrillary tangles, isthe basis for definitive pathological diagnosis of AD.

The major components of amyloid plaques are the amyloid Aβ-peptides,also called Aβ-peptides, that consist of several proteins including 38,40, 42 or 43 amino acids, designated as the Aβ₁₋₃₈, Aβ₁₋₄₀, Aβ₁₋₄₂ andAβ₁₋₄₃ peptides, respectively. The Aβ-peptides are thought to causenerve cell destruction, in part, because they are toxic to neurons invitro and in vivo.

The Aβ peptides are derived from larger amyloid precursor proteins (APPproteins), that consist of four proteins containing 695, 714, 751 or 771amino acids, designated as the APP₆₉₅, APP₇₁₄, APP₇₅₁ and APP₇₇₁,respectively. Proteases are believed to produce the Aβ peptides bycleaving specific amino acid sequences within the various APP proteins.The proteases are named “secretases” because the Aβ-peptides theyproduce are secreted by cells into the extracellular environment. Thesesecretases are each named according to the cleavage(s) they make toproduce the Aβ-peptides. The secretase that forms the amino terminal endof the Aβ-peptides is called the beta-secretase. The secretase thatforms the carboxyl terminal end of the Aβ-peptides is called thegamma-secretase.

This invention relates to novel compounds that inhibit Aβ-peptideproduction, to pharmaceutical compositions comprising such compounds,and to methods of using such compounds to treat neurodegenerative and/orneurological disorders.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the Formula I

-   -   wherein A is absent or is selected from        and 502.    -   Z is selected from —CH₂, —CH(OH), —CH(C₁-C₆ alkyl), —CH(C₁-C₆        alkoxy), —CH(NR⁹R¹⁰), —CH(CH₂(OH)), —CH(CH(C₁-C₄ alkyl)(OH)) and        —CH(C(C₁-C₄ alkyl)(C₁-C₄alkyl)(OH)), for example        —CH(C(CH₃)(CH₃)(OH)) or —CH(C(CH₃)(CH₂CH₃)(OH));    -   R¹ is selected from C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀        alkynyl, C₁-C₂₀ alkoxy, C₂-C₂₀ alkenoxy, C₁-C₂₀ hydroxyalkyl,        C₃-C₈ cycloalkyl, benzo(C₃-C₈ cycloalkyl), benzo(C₃-C₈        heterocycloalkyl), C₄-C₈ cycloalkenyl, (C₅-C₁₁)bi- or        tricycloalkyl, benzo(C₅-C₁₁)bi- or tricycloalkyl, (C₇-C₁₁)bi- or        tricycloalkenyl, (3-8 membered) heterocycloalkyl, C₆-C₁₄ aryl        and (5-14 membered) heteroaryl, wherein each hydrogen atom of        said alkyl, alkenyl, alkynyl, alkoxy and alkenoxy is optionally        independently replaced with halo, and wherein said cycloalkyl,        benzo(C₃-C₈ cycloalkyl), cycloalkenyl, (3-8 membered)        heterocycloalkyl, C₆-C₁₄ aryl and (5-14 membered) heteroaryl is        optionally independently substituted with from one to four        substituents independently selected from C₁-C₁₀ alkyl optionally        substituted with from one to three halo atoms, C₁-C₁₀ alkoxy        optionally substituted with from one to three halo atoms, C₁-C₁₀        hydroxyalkyl, halo, preferably fluorine, —OH, —CN, —NR⁹R¹⁰,        —C(═O)NR⁹R¹⁰, —C(═O)R¹¹, C₃-C₈ cycloalkyl and (3-8 membered)        heterocycloalkyl;    -   R² is selected from H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₈        cycloalkyl and C₅-C₈ cycloalkenyl, wherein R² is optionally        independently substituted with from one to three substituents        independently selected from C₁-C₄ alkyl optionally substituted        with from one to three halo atoms, C₁-C₄ alkoxy optionally        substituted with from one to three halo atoms, halo and —OH;    -   or R¹ and R² together with the A group when present and the        nitrogen atom to which R² is attached, or R¹ and R² together        with the nitrogen atom to which R¹ and R¹² are attached when A        is absent, may optionally form a four to eight membered ring;    -   R³ is selected from H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, C₃-C₆ cycloalkyl, C₅-C₆ cycloalkenyl and (3-8 membered)        heterocycloalkyl, wherein said alkyl, alkenyl, alkynyl,        cycloalkyl, cycloalkenyl and heterocycloalkyl are each        optionally independently substituted with from one to three        substituents independently selected from C₁-C₄ alkoxy, halo, —OH        —S(C₁-C₄)alkyl and (3-8 membered) heterocycloalkyl;    -   R⁴ is H, C₁-C₆ alkyl or halo;    -   or R³ and R⁴ may together with the carbon atom to which they are        attached optionally form a moiety selected from cyclopropyl,        cyclobutyl, cyclopentyl, cyclohexyl, morpholino, piperidino,        pyrrolidino, tetrahydrofuranyl and perhydro-2H-pyran, wherein        said moiety formed by R³ and R⁴ is optionally substituted with        from one to three substituents independently selected from C₁-C₆        alkyl optionally substituted with from one to three halo atoms,        C₁-C₆ alkoxy optionally substituted with from one to three halo        atoms, halo, —OH, —CN and allyl;    -   R⁶ is selected from H, C₁-C₆ alkyl, C₂-C₆ alkylene, C₁-C₆        alkoxy, halo, —CN, C₃-C₁₂ cycloalkyl, C₄-C₁₂ cycloalkenyl and        C₆-C₁₀ aryl, (5-10 membered) heteroaryl, wherein said alkyl,        alkylene and alkoxy of R⁶ are each optionally independently        substituted with from one to three substituents independently        selected from halo and —CN, and wherein said cycloalkyl,        cycloalkenyl and aryl and heteroaryl of R⁶ are each optionally        independently substituted with from one to three substituents        independently selected from C₁-C₄ alkyl optionally substituted        with from one to three halo atoms, C₁-C₄ alkoxy optionally        substituted with from one to three halo atoms, halo and —CN;    -   R⁷ is selected from H, C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy, C₁-C₂₀        hydroxyalkyl, C₃-C₁₂ cycloalkyl, C₄-C₁₂ cycloalkenyl, (C₅-C₂₀)        bi- or tricycloalkyl, (C₇-C₂₀)bi- or tricycloalkenyl, (3-12        membered) heterocycloalkyl, (7-20 membered) heterobi- or        heterotricycloalkyl, C₆-C₁₄ aryl and (5-15 membered) heteroaryl,        wherein R⁷ is optionally independently substituted with from one        to four substituents independently selected from C₁-C₂₀ alkyl        optionally substituted with from one to three halo atoms, C₁-C₂₀        alkoxy, —OH, —CN, —NO₂, —NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, —C(═O)R¹¹,        —C(═O)OR¹¹, —S(O)_(n)NR⁹R¹⁰, —S(O)_(n)R¹¹, C₃-C₁₂ cycloalkyl,        (4-12 membered) heterocycloalkyl optionally substituted with        from one to three OH or halo groups, (4-12 membered)        heterocycloalkoxy, C₆-C₁₄ aryl, (5-15 membered) heteroaryl,        C₆-C₁₂ aryloxy and (5-12 membered) heteroaryloxy;    -   or R⁶ and R⁷ may together with the carbon and nitrogen atoms to        which they are respectively attached optionally form a (5-8        membered) heterocycloalkyl ring, a (5-8 membered)        heterocycloalkenyl ring or a (6-10 membered) heteroaryl ring,        wherein said heterocycloalkyl, heterocycloalkenyl and heteroaryl        rings are each optionally independently substituted with from        one to three substituents independently selected from halo,        C₁-C₆ alkyl, optionally subsituted with from one to three halo        atoms, C₁-C₆ alkoxy optionally subsituted with from one to three        halo atoms, C₁-C₆ hydroxyalkyl, —OH, —(CH₂)_(zero-10)NR⁹R¹⁰,        —(CH₂)_(zero-10)C(═O)NR⁹R¹⁰, —SO₂NR⁹R¹⁰ and C₃-C₁₂ cycloalkyl;    -   R⁹ and R¹⁰ are each independently selected from H, C₁-C₁₀ alkyl        wherein each hydrogen atom of said C₁-C₁₀ alkyl is optionally        independently replaced with a halo atom, preferably a fluorine        atom, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₆ alkoxy wherein each        hydrogen atom of said C₁-C₆ alkoxy is optionally independently        replaced with a halo atom, C₂-C₆ alkenoxy, C₂-C₆ alkynoxy,        —C(═O)R¹¹, —S(O)_(n)R¹¹, C₃-C₈ cycloalkyl, C₄-C₈ cycloalkenyl,        (C₅-C₁₁)bi- or tricycloalkyl, (CrC₁₁)bi- or tricycloalkenyl,        (3-8 membered) heterocycloalkyl, C₆-C₁₄ aryl and (5-14 membered)        heteroaryl, wherein said alkyl and alkoxy are each optionally        independently substituted with from one to three substituents        independently selected from halo and —OH, and wherein said        cycloalkyl, cycloalkenyl, bi- or tricycloalkyl, bi- or        tricycloalkenyl, heterocycloalkyl, aryl and heteroaryl are each        optionally independently substituted with from one to three        substituents independently selected from halo, —OH, C₁-C₆ alkyl        optionally independently substituted with from one to six halo        atoms, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₂-C₆        alkenoxy, C₂-C₆ alkynoxy and C₁-C₆ hydroxyalkyl;    -   or NR⁹R¹⁰ may form a (4-7 membered) heterocycloalkyl, wherein        said heterocycloalkyl optionally comprises from one to two        further heteroatoms independently selected from N, O and S, and        wherein said heterocycloalkyl optionally contains from one to        three double bonds, and wherein said heterocycloalkyl is        optionally independently substituted with from one to three        substituents independently selected from C₁-C₆ alkyl optionally        substituted with from one to six halo atoms, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₂-C₆ alkenoxy, C₂-C₆ alkynoxy,        C₁-C₆ hydroxyalkyl, C₂-C₆ hydroxyalkenyl, C₂-C₆ hydroxyalkynyl,        halo, —OH, —CN, —NO₂, —C(═O)R¹¹, —C(═O)OR¹¹, —S(O)_(n)R¹¹ and        —S(O)_(n)NR⁹R¹⁰;    -   R¹¹ is selected from H, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₄-C₈        cycloalkenyl, (C₅-C₁₁)bi- or tricycloalkyl, —(C₇-C₁₁)bi- or        tricycloalkenyl, (3-8 membered) heterocycloalkyl, C₆-C₁₀ aryl        and (5-14 membered) heteroaryl, wherein said alkyl of R¹¹ is        optionally independently substituted with from one to three        substituents independently selected from —OH, —CN and C₃-C₈        cycloalkyl, and wherein each hydrogen atom of said alkyl is        optionally independently replaced with a halo atom, preferably a        fluorine atom, and wherein said cylcoalkyl, cycloalkenyl,        heterocycloalkyl, aryl and hetereoaryl of R¹¹ are each        optionally independently substituted with from one to three        substituents independently selected from halo, C₁-C₈ alkyl        optionally substituted with from one to three halo atoms, —OH,        —CN and C₃-C₈ cycloalkyl;    -   n is in each instance an integer independently selected from        zero, 1, 2 and 3;    -   and the pharmaceutically acceptable salts of such compounds.

Compounds of the Formula I may have optical centers and therefore mayoccur in different enantiomeric and diastereomeric configurations. Thepresent invention includes all enantiomers, diastereomers, and otherstereoisomers of such compounds of the Formula I, as well as racemiccompounds and racemic mixtures and other mixtures of stereoisomersthereof.

Pharmaceutically acceptable salts of the compounds of Formula I includethe acid addition and base salts thereof.

Suitable acid addition salts are formed from acids which form non-toxicsalts. Examples include, but are not limited to, the acetate, adipate,aspartate, benzoate, besylate, bicarbonate/carbonate,bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate,esylate, formate, fumarate, gluceptate, gluconate, glucuronate,hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mandelates mesylate, methylsulphate, naphthylate,2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate,salicylate, saccharate, stearate, succinate, sulfonate, stannate,tartrate, tosylate, trifluoroacetate and xinofoate salts.

Suitable base salts are formed from bases which form non-toxic salts.Examples include, but are not limited to, the aluminium, arginine,benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine,magnesium, meglumine, olamine, potassium, sodium, tromethamine and zincsalts.

Hemisalts of acids and bases may also be formed, for example,hemisulphate and hemicalcium salts.

For a review on suitable salts, see Handbook of Pharmaceutical Salts:Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).

Pharmaceutically acceptable salts of compounds of Formula I may beprepared by one or more of three methods:

-   -   (i) by reacting the compound of Formula I with the desired acid        or base;    -   (ii) by removing an acid- or base-labile protecting group from a        suitable precursor of the compound of Formula I or by        ring-opening a suitable cyclic precursor, for example, a lactone        or lactam, using the desired acid or base; or    -   (iii) by converting one salt of the compound of Formula I to        another by reaction with an appropriate acid or base or by means        of a suitable ion exchange column.

All three reactions are typically carried out in solution. The resultingsalt may precipitate out and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionization in theresulting salt may vary from completely ionised to almost non-ionised.

The compounds of the invention may exist in a continuum of solid statesranging from fully amorphous to fully crystalline. The term ‘amorphous’refers to a state in which the material lacks long range order at themolecular level and, depending upon temperature, may exhibit thephysical properties of a solid or a liquid. Typically such materials donot give distinctive X-ray diffraction patterns and, while exhibitingthe properties of a solid, are more formally described as a liquid. Uponheating, a change from solid to liquid properties occurs which ischaracterised by a change of state, typically second order (‘glasstransition’). The term ‘crystalline’ refers to a solid phase in whichthe material has a regular ordered internal structure at the molecularlevel and gives a distinctive X-ray diffraction pattern with definedpeaks. Such materials when heated sufficiently will also exhibit theproperties of a liquid, but the change from solid to liquid ischaracterised by a phase change, typically first order (‘meltingpoint’).

The compounds of the invention may also exist in unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and one or morepharmaceutically acceptable solvent molecules, for example, ethanol. Theterm ‘hydrate’ is employed when said solvent is water.

A currently accepted classification system for organic hydrates is onethat defines isolated site, channel, or metal-ion coordinatedhydrates—see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed.H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones inwhich the water molecules are isolated from direct contact with eachother by intervening organic molecules. In channel hydrates, the watermolecules lie in lattice channels where they are next to other watermolecules. In metal-ion coordinated hydrates, the water molecules arebonded to the metal ion.

When the solvent or water is tightly bound, the complex will have awell-defined stoichiometry independent of humidity. When, however, thesolvent or water is weakly bound, as in channel solvates and hygroscopiccompounds, the water/solvent content will be dependent on humidity anddrying conditions. In such cases, non-stoichiometry will be the norm.

The compounds of the invention may also exist in a mesomorphic state(mesophase or liquid crystal) when subjected to suitable conditions. Themesomorphic state is intermediate between the true crystalline state andthe true liquid state (either melt or solution). Mesomorphism arising asthe result of a change in temperature is described as ‘thermotropic’ andthat resulting from the addition of a second component, such as water oranother solvent, is described as ‘Iyotropic’. Compounds that have thepotential to form lyotropic mesophases are described as ‘amphiphilic’and consist of molecules which possess an ionic (such as —COO⁻Na⁺,—COO⁻K⁺, or —SO₃ ⁻Na⁺) or non-ionic (such as —N⁻N⁺(CH₃)₃) polar headgroup. For more information, see Crystals and the Polarizing Microscopeby N. H. Hartshorne and A. Stuart, 4^(th) Edition (Edward Arnold, 1970).

Hereinafter all references to compounds of Formula I include referencesto salts, solvates, multi-component complexes and liquid crystalsthereof and to solvates, multi-component complexes and liquid crystalsof salts thereof.

The compounds of the invention include compounds of Formula I ashereinbefore defined, including all polymorphs and crystal habitsthereof, prodrugs and isomers thereof (including optical, geometric andtautomeric isomers) as hereinafter defined and isotopically-labeledcompounds of Formula I.

Unless otherwise indicated, as used herein, the term “A is absent” meansa direct bond between the nitrogen and R¹ (i.e., —N—R¹).

Unless otherwise indicated, as used herein, the term “alkyl” includessaturated monovalent hydrocarbon radicals having straight or branchedmoieties. Examples of alkyl groups include, but are not limited to,methyl, ethyl, n-propyl, isopropyl, and t-butyl.

Unless otherwise indicated, as used herein, the term “alkenyl” includesalkyl moieties having at least one carbon-carbon double bond whereinalkyl is as defined above. Examples of alkenyl include, but are notlimited to, ethenyl and propenyl.

Unless otherwise indicated, as used herein, the term “alkynyl” includesalkyl moieties having at least one carbon-carbon triple bond whereinalkyl is as defined above. Examples of alkynyl groups include, but arenot limited to, ethynyl and 2-propynyl.

Unless otherwise indicated, as used herein, the term “alkoxy”, means“alkyl-O-”, wherein “alkyl” is as defined above. Examples of “alkoxy”groups include, but are not limited to, methoxy, ethoxy, propoxy,butoxy, pentoxy and allyloxy.

Unless otherwise indicated, as used herein, the term “alkenoxy”, means“alkenyl-O-”, wherein “alkenyl” is as defined above.

Unless otherwise indicated, as used herein, the term “cycloalkyl”includes non-aromatic saturated cyclic alkyl moieties wherein alkyl isas defined above. Examples of cycloalkyl include, but are not limitedto, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.“Bicycloalkyl” and “tricycloalkyl” groups are non-aromatic saturatedcarbocyclic groups consisting of two or three rings respectively,wherein said rings share at least one carbon atom. Unless otherwiseindicated, for purposes of the present invention, bicycloalkyl groupsinclude spiro groups and fused ring groups. Examples of bicycloalkylgroups include, but are not limited to, bicyclo-[3.1.0]-hexyl,bicyclo-2.2.1]-hept-1-yl, norbornyl, spiro[4.5]decyl, spiro[4.4]nonyl,spiro[4.3]octyl, and spiro[4.2]heptyl. An example of a tricycloalkylgroup is adamantanyl. Other cycloalkyl, bicycloalkyl, and tricycloalkylgroups are known in the art, and such groups are encompassed by thedefinitions “cycloalkyl”, “bicycloalkyl” and “tricycloalkyl” herein.

“Cycloalkenyl”, “bicycloalkenyl”, and “tricycloalkenyl” refer tonon-aromatic carbocyclic cycloalkyl, bicycloalkyl, and tricycloalkylmoieties as defined above, except comprising one or more carbon-carbondouble bonds connecting carbon ring members (an “endocyclic” doublebond) and/or one or more carbon-carbon double bonds connecting a carbonring member and an adjacent non-ring carbon (an “exocyclic” doublebond). Examples of cycloalkenyl groups include, but are not limited to,cyclopentenyl, cyclobutenyl, and cyclohexenyl, and a non-limitingexample of a bicycloalkenyl group is norbornenyl. Other cycloalkenyl,bicycloalkenyl, and tricycloalkenyl groups are known in the art, andsuch groups are included within the definitions “cycloalkenyl”,“bicycloalkenyl” and “tricycloalkenyl” herein.

Cycloalkyl, cycloalkenyl, bicycloalkyl, and bicycloalkenyl groups alsoinclude groups that are substituted with one or more oxo moieties.Examples of such groups with oxo moieties are oxocyclopentyl,oxocyclobutyl, oxocyclopentenyl, and norcamphoryl.

As used herein, the term “benzocycloalkyl” includes, without limitation,moieties such as tetrahydronaphthyl, indanyl, 1,2-benzocylcoheptanyl andthe like.

Unless otherwise indicated, as used herein, the term “aryl” includes anorganic radical derived from an aromatic hydrocarbon by removal of onehydrogen, such as phenyl, naphthyl, indenyl, indanyl, and fluorenyl.“Aryl” encompasses fused ring groups wherein at least one ring isaromatic.

Unless otherwise indicated, as used herein, the terms “heterocyclic” and“heterocycloalkyl” refer to non-aromatic cyclic groups containing one ormore heteroatoms, prefereably from one to four heteroatoms, eachselected from O, S and N. “Heterobicycloalkyl” groups are non-aromatictwo-ringed cyclic groups, wherein said rings share one or two atoms, andwherein at least one of the rings contains a heteroatom (O, S, or N).Heterobicycloalkyl groups for purposes of the present invention, andunless otherwise indicated, include spiro groups and fused ring groups.“Heterotricycloalkyl” groups are non-aromatic three-ringed cyclicgroups, wherein said rings are fused to one another or form a spirogroup (in other words, at least two of said rings share one or two atomsand the third ring shares one or two atoms with at least one of said tworings). The heterotricycloalkyl groups of the compounds of the presentinvention can include one or more O, S and/or N heteroatoms. In oneembodiment, each ring in the heterobicycloalkyl or heterotricycloalkylcontains up to four heteroatoms (i.e. from zero to four heteroatoms,provided that at least one ring contains at least one heteroatom). Theheterocycloalkyl, heterobicycloalky and heterotricycloalkyl groups ofthe present invention can also include ring systems substituted with oneor more oxo moieties. The heterocyclic groups, including theheterobicyclic and heterotricyclic groups, may comprise double or triplebonds, e.g. heterocycloalkenyl, heterobicycloalkenyl, andheterotricycloalkenyl. Examples of non-aromatic heterocyclic groups areaziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl,piperazinyl, 1,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, morpholino, thiomorpholino, thioxanyl,pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl,pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, quinolizinyl, quinuclidinyl,1,4-dioxaspiro[4.5]decyl, 1,4-dioxaspiro[4.4]nonyl,1,4-dioxaspiro[4.3]octyl, and 1,4-dioxaspiro[4.2]heptyl.

Unless otherwise indicated, as used herein, “heteroaryl” refers toaromatic groups containing one or more heteroatoms (O, S, or N),preferably from one to four heteroatoms. A multicyclic group containingone or more heteroatoms wherein at least one ring of the group isaromatic is a “heteroaryl” group. The heteroaryl groups of thisinvention can also include ring systems substituted with one or more oxomoieties. Examples of heteroaryl groups are pyridinyl, pyridazinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl,isoquinolyl, 1,2,3,4-tetrahydroguinolyl, tetrazolyl, furyl, thienyl,isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, triazinyl, 1,2,4-trizainyl, 1,3,5-triazinyl, isoindolyl,1-oxoisoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl,dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl,tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrolopyrimidinyl, andazaindolyl.

As appreciated by the artisan, the use of Formula I is a convenience,and the invention is understood to envision and embrace each and everyspecies thereunder as though individually identified and set forthherein. Thus, the present invention contemplates each species separatelyand any and all combinations and permutations of species falling withinFormula I.

The foregoing groups, as derived from the compounds listed above, may beC-attached or N-attached where such is possible. For instance, a groupderived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl(C-attached). The terms referring to the groups also encompass allpossible tautomers.

As indicated, so-called ‘prodrugs’ of the compounds of Formula I arealso within the scope of the invention. Thus certain derivatives ofcompounds of Formula I which may have little or no pharmacologicalactivity themselves can, when administered into or onto the body, beconverted into compounds of Formula I having the desired activity, forexample, by hydrolytic cleavage. Such derivatives are referred to as‘prodrugs’. Further information on the use of prodrugs may be found inPro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T.Higuchi and W. Stella) and Bioreversible Carriers in Drug Design,Pergamon Press, 1987 (Ed. E. B. Roche, American PharmaceuticalAssociation).

Prodrugs in accordance with the invention can, for example, be producedby replacing appropriate functionalities present in the compounds ofFormula I with certain moieties known to those skilled in the art as‘pro-moieties’ as described, for example, in Design of Prodrugs by H.Bundgaard (Elsevier, 1985).

Some examples of prodrugs in accordance with the invention include, butare not limited to,

-   -   (i) where the compound of Formula I contains a carboxylic acid        functionality (—COOH), an ester thereof, for example, a compound        wherein the hydrogen of the carboxylic acid functionality of the        compound of Formula (I) is replaced by (C₁-C₈)alkyl;    -   (ii) where the compound of Formula I contains an alcohol        functionality (—OH), an ether thereof, for example, a compound        wherein the hydrogen of the alcohol functionality of the        compound of Formula I is replaced by (C₁-C₆)alkanoyloxymethyl;        and    -   (iii) where the compound of Formula I contains a primary or        secondary amino functionality (—NH₂ or —NHR where R≈H), an amide        thereof, for example, a compound wherein, as the case may be,        one or both hydrogens of the amino functionality of the compound        of Formula I is/are replaced by (C₁-C₁₀)alkanoyl.

Further examples of replacement groups in accordance with the foregoingexamples and examples of other prodrug types may be found in theaforementioned references.

Moreover, certain compounds of Formula I may themselves act as prodrugsof other compounds of Formula I.

Also included within the scope of the invention are metabolites ofcompounds of Formula I, that is, compounds formed in vivo uponadministration of the drug. Some examples of metabolites in accordancewith the invention include, but are not limited to,

-   -   (i) where the compound of Formula I contains a methyl group, an        hydroxymethyl derivative thereof (—CH₃—>—CH₂OH):    -   (ii) where the compound of Formula I contains an alkoxy group,        an hydroxy derivative thereof (—OR—>—OH);    -   (iii) where the compound of Formula I contains a tertiary amino        group, a secondary amino derivative thereof (—NR¹R²—>—NHR¹ or        —NHR²);    -   (iv) where the compound of Formula I contains a secondary amino        group, a primary derivative thereof (—NHR¹—>—NH₂);    -   (v) where the compound of Formula I contains a phenyl moiety, a        phenol derivative thereof (-Ph->-PhOH); and    -   (vi) where the compound of Formula I contains an amide group, a        carboxylic acid derivative thereof (—CONH₂->COOH).

Compounds of Formula I containing one or more asymmetric carbon atomscan exist as two or more stereoisomers. Where a compound of Formula Icontains an alkenyl or alkenylene group, geometric cis/trans (or Z/E)isomers are possible. Where structural isomers are interconvertible viaa low energy barrier, tautomeric isomerism (‘tautomerism’) can occur.This can take the form of proton tautomerism in compounds of Formula Icontaining, for example, an imino, keto, or oxime group, or so-calledvalence tautomerism in compounds which contain an aromatic moiety. Itfollows that a single compound may exhibit more than one type ofisomerism.

Included within the scope of the present invention are allstereoisomers, geometric isomers and tautomeric forms of the compoundsof Formula I, including compounds exhibiting more than one type ofisomerism, and mixtures of one or more thereof. Also included are acidaddition or base salts wherein the counterion is optically active, forexample, d-lactate or I-lysine, or racemic, for example, dl-tartrate ordl-arginine.

Cis/trans isomers may be separated by conventional techniques well knownto those skilled in the art, for example, chromatography and fractionalcrystallisation.

Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor or resolution of the racemate (or the racemate of a salt orderivative) using, for example, chiral high pressure liquidchromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted witha suitable optically active compound, for example, an alcohol, or, inthe case where the compound of Formula I contains an acidic or basicmoiety, a base or acid such as 1-phenylethylamine or tartaric acid. Theresulting diastereomeric mixture may be separated by chromatographyand/or fractional crystallization and one or both of thediastereoisomers converted to the corresponding pure enantiomer(s) bymeans well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may beobtained in enantiomerically-enriched form using chromatography,typically HPLC, on an asymmetric resin with a mobile phase consisting ofa hydrocarbon, typically heptane or hexane, containing from 0 to 50% byvolume of isopropanol, typically from 2% to 20%, and from 0 to 5% byvolume of an alkylamine, typically 0.1% diethylamine. Concentration ofthe eluate affords the enriched mixture.

When any racemate crystallises, crystals of two different types arepossible. The first type is the racemic compound (true racemate)referred to above wherein one homogeneous form of crystal is producedcontaining both enantiomers in equimolar amounts. The second type is theracemic mixture or conglomerate wherein two forms of crystal areproduced in equimolar amounts each comprising a single enantiomer.

While both of the crystal forms present in a racemic mixture haveidentical physical properties, they may have different physicalproperties compared to the true racemate. Racemic mixtures may beseparated by conventional techniques known to those skilled in theart—see, for example, Stereochemistry of Organic Compounds by E. L.Eliel and S. H. Wilen (Wiley, 1994).

The present invention includes all pharmaceutically acceptableisotopically-labelled compounds of Formula I wherein one or more atomsare replaced by atoms having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number whichpredominates in nature.

Examples of isotopes suitable for inclusion in the compounds of theinvention include, but are not limited to, isotopes of hydrogen, such as²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl,fluorine, such as ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P,and sulphur, such as ³⁵S.

Certain isotopically-labelled compounds of Formula I, for example, thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium, i.e. ³H,and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose inview of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy.

Isotopically-labeled compounds of Formula I can generally be prepared byconventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examples andPreparations using an appropriate isotopically-labeled reagent in placeof the non-labeled reagent previously employed.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Also within the scope of the invention are intermediate compounds ofFormula II as hereinbefore defined, all salts, solvates and complexesthereof and all solvates and complexes of salts thereof as definedhereinbefore for compounds of Formula I. The invention includes allpolymorphs of the aforementioned species and crystal habits thereof.

When preparing compounds of Formula I in accordance with the invention,it is open to a person skilled in the art to routinely select the formof compound of Formula II which provides the best combination offeatures for this purpose. Such features include, but are not limitedto, the melting point, solubility, processability and yield of theintermediate form and the resulting ease with which the product may bepurified on isolation.

In one aspect, the present invention relates to compounds of the FormulaI wherein A is absent or is

Z is —CH₂, —CH(OH) or —CH(C₁-C₆ alkyl); R¹ is C₁-C₁₀ alkyl, C₆-C₁₀ aryl,(6-10 membered) heteroaryl or benzo(C₅-C₆ cycloalkyl), wherein when R¹is C₆-C₁₀ aryl, C₆-C₁₀ heteroaryl or benzo(C₅-C₆ cycloalkyl), R¹ isoptionally independently substituted with from one to three substituentsindependently selected from C₁-C₆ alkyl, halo, preferably fluorine, andOH; R² is H or C₁-C₆ alkyl; R³ is H, —CH₂CH₂SCH₃, —O(C₁-C₄)alkyl orC₁-C₆ alkyl; R⁴ is H or C₁-C₈ alkyl; R⁶ is H or C₁-C₆ alkyl; R⁷ isC₁-C₁₀ alkyl, C₃-C₈ cycloalkyl or (4-10 membered) heterocycloalkyl,wherein R⁷ is optionally independently substituted with from one tothree substituents independently selected from C₁-C₈ alkyl, C₁-C₈alkoxy, OH, —NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, —C(═O)R¹¹, —C(═O)OR¹¹ and (4-6membered) heterocycloalkyl optionally substituted with from one to threeOH or halo groups; and R⁹, R¹⁰ and R¹¹ are each independently selectedfrom H and C₁-C₆ alkyl, wherein each hydrogen atom of said C₁-C₆ alkylis optionally independently replaced with a halo atom, preferably afluorine atom.

In another aspect, A is absent or is

Z is —CH₂ or —CH(OH); R¹ is C₁-C₁₀ alkyl, C₆-C₁₀ aryl or benzo(C₅-C₆cycloalkyl), wherein when R¹ is C₆-C₁₀ aryl or benzo(C₅-C₆ cycloalkyl),R¹ is optionally independently substituted with from one to threeindependently selected halo substituents, preferably fluorine; R² is Hor C₁-C₆ alkyl; R³ is H or C₁-C₆ alkyl; R⁴ is H or C₁-C₆ alkyl; R⁶ is Hor C₁-C₆ alkyl; R⁷ is C₁-C₁₀ alkyl or (4-10 membered) heterocycloalkyl,wherein R⁷ is optionally independently substituted with from one tothree substituents independently selected from C₁-C₈ alkyl, C₁-C₈alkoxy, OH, —NR⁹R¹⁰, —C(═O)R¹¹, —C(═O)OR¹¹ and (4-6 membered)heterocycloalkyl optionally substituted with from one to three OHgroups; and R⁹, R¹⁰ and R¹¹ are each independently selected from H andC₁-C₆ alkyl, wherein each hydrogen atom of said C₁-C₆ alkyl isoptionally independently replaced with a halo atom, preferably afluorine atom.

In another aspect, the present invention relates to compounds of theFormula I wherein A is absent; R¹ is benzo(C₅-C₆ alkyl) optionallysubstituted with from one to three substituents independently selectedfrom C₁-C₆ alkyl, halo, preferably fluorine and OH; R² is H or C₁-C₆alkyl; R³ is H or C₁-C₆ alkyl; R⁴ is H or C₁-C₆ alkyl; R⁶ is H or C₁-C₆alkyl; R⁷ is C, —C₁₀ alkyl, wherein R⁷ is optionally independentlysubstituted with from one to three substituents independently selectedfrom C₁-C₈ alkoxy, OH, —NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, —C(═O)R¹¹ and —C(═O)OR¹¹.

In another aspect, A is absent; ¹ is benzo(C₅-C₆ alkyl) optionallysubstituted with from one to three independently selected halosubstituents, preferably fluorine; R² is H or C₁-C₆ alkyl; R³ is H,—CH₂CH₂SCH₃—O(C₁-C₄)alkyl or C₁-C₆ alkyl; R⁴ is H or C₁-C₆ alkyl; R⁶ isH or C₁-C₆ alkyl; R⁷ is C₁-C₁₀ alkyl, wherein R⁷ is optionallyindependently substituted with from one to three substituentsindependently selected from C₁-C₈ alkoxy, OH, —NR⁹R¹⁰, —C(═O)NR⁹R¹⁰,—C(═O)R¹¹, —C(═O)OR¹¹ and (4-6 membered) heterocycloalkyl.

In another aspect, R¹ is 1, 2, 3, 4-tetrahydronaphthalene or indanyloptionally substituted with 1 to 3 fluorine or chlorine atoms.

In another aspect, the present invention relates to compounds of theFormula I wherein A is

Z is —CH₂, —CH(OH) or —CH(C₁-C₆ alkyl); R¹ is C₁-C₁₀ alkyl, C₆-C₁₀ arylor (6-10 membered) heteroaryl, wherein said alkyl, aryl and heteroarylare optionally independently substituted with from one to threesubstituents independently selected from C₁-C₆ alkyl, halo, preferablyfluorine and OH; R¹ is H or C₁-C₆ alkyl; R³ is H or C₁-C₆ alkyl; R⁴ is Hor C₁-C₆ alkyl; R⁶ is H or C₁-C₆ alkyl; R⁷ is C₁-C₁₀ alkyl, C₃-C₈cycloalkyl or (4-10 membered) heterocycloalkyl, wherein R⁷ is optionallyindependently substituted with from one to three substituentsindependently selected from C₁-C₈ alkyl, C₁-C₈ alkoxy, OH, —NR⁹R¹⁰,—C(═O)NR⁹R¹⁰, —C(═O)R¹¹, —C(═O)OR¹¹ and (4-6 membered) heterocycloalkyloptionally substituted with from one to three OH or halo groups.

In another aspect, A is

Z is —CH₂ or —CH(OH); R¹ is C₁-C₁₀ alkyl or C₆-C₁₀ aryl, wherein saidalkyl and aryl are optionally independently substituted with from one tothree independently selected halo substituents, preferably fluorine; R²is H or C₁-C₆ alkyl; R³ is H or C₁-C₆ alkyl; R⁴ is H or C₁-C₆ alkyl; R⁶is H or C₁-C₆ alkyl; R⁷ is C₁-C₁₀ alkyl or (4-10 membered)heterocycloalkyl, wherein R⁷ is optionally independently substitutedwith from one to three substituents independently selected from C₁-C₈alkyl, C₁-C₈ alkoxy, OH, —NR⁹R¹⁰, —C(═O)R¹¹, —C(═O)OR¹¹ and (4-6membered) heterocycloalkyl optionally substituted with from one to threeOH groups.

In another aspect, the (4-10 membered) heterocycloalkyl group of R⁷ isazetidinyl, pyrrolidinyl or piperidinyl; and the (4-6 membered)heterocycloalkyl substituent of R⁷ is morpholino pyrrolidinyl orpiperidinyl.

In another aspect, —R⁷ is a C₁-C₆ alkyl optionally substituted with—NR⁹R¹⁰, morpholino, pyrrolidinyl or piperidinyl.

In another aspect, R⁴ is H and R³ is methyl, ethyl butyl, isobutyl,propyl, isopropyl, —CH₂CH₂SCH₃ or —CH₂CH₂OCH₃.

In another aspect, wherein R¹ is aryl, A is

Z is —CH₂, and R⁷ is a C₁-C₆ alkyl optionally substituted with —NR⁹R¹⁰,morpholino, pyrrolidinyl or piperidinyl.

In another aspect, the compound of Formula I has the followingstructure, where the stereochemistry of the R³ and R⁴ substituents areshown below:

In another aspect, in the stereochemistry structure above, R⁴ and R² arehydrogen.

Specific embodiments of the present invention include the followingcompounds of Formula I, all pharmaceutically acceptable salts thereof,complexes thereof, and derivatives thereof that convert into apharmaceutically active compound upon administration:

-   3-(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl-butyric    acid methyl ester;    -   3-{4-[2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoylamino]-imidazol-1-yl}-3-methyl-butyric        acid methyl ester;-   3-(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-3-methyl-butyric    acid methyl ester;-   3-{4-[2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoylamino]-imidazol-1-yl}-3-methyl-butyric    acid methyl ester;-   2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid    [1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid    [1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide;-   2-(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-2-methyl-propionic    acid methyl ester;-   2-(4-{2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoylamino}-imidazol-1-yl-2-methyl-propionic    acid methyl ester;-   2-{4-[2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoylamino]-imidazol-1-yl}-2-methyl-propionic    acid methyl ester;-   2-{4-[2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoylamino]-imidazol-1-yl}-2-methyl-propionic    acid methyl ester;-   3-(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-propionylamino}-imidazol-1-yl)-3-methyl-butyric    acid methyl ester;-   3-{4-[2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-propionylamino]-imidazol-1-yl}-3-methyl-butyric    acid methyl ester;-   4-(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-piperidine-1-carboxylic    acid tert-butyl ester;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3-Trifluoromethyl-phenyl)-acetylamino]-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3-Trifluoromethoxy-phenyl)-acetylamino]-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid    [1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide;-   2-[2-(4-Phenyl-th iazol-2-yl)-acetylamino]-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3-Trifluoromethyl-phenyl)-acetylamino]-pentanoic acid    [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid    [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid    [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid    [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]4-methyl-pentanoic acid    [1-(1,1-dimethyl-2-pyrrol id in-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-propionamide;-   (4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-acetic    acid methyl ester;-   2-(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-2-methyl-imidazol-1-yl)-2-methyl-propionic    acid methyl ester;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(2-methoxy-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide;-   4-(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-benzoic    acid methyl ester;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    {1-[1-(2,2-dimethyl-propyl)-pyrrolidin-3-yl]-1H-imidazol-4-yl}-amide;-   3-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoylamino]-imidazol-1-yl}-butyric    acid methyl ester;-   2-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoylamino]-imidazol-1-yl}-2-methyl-propionic    acid methyl ester;-   2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid [1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide;-   3-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoylamino]-imidazol-1-yl}-3-methyl-butyric    acid methyl ester;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(2-isopropylamino-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(1,1-dimethyl-2-methylamino-ethyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(2-benzylamino-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    {1-[2-(2,2-dimethyl-propylamino)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(2-dimethylamino-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    {1-[1,1-dimethyl-2-(1-phenyl-ethylamino)-ethyl]-1H-imidazol-4-yl}-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(1,1-dimethyl-3-morpholin-4-yl-propyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(1,1-dimethyl-3-pyrrolidin-1-yl-propyl)-1H-imidazol-4-yl]-amide;-   2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(5-Chloro-indan-2-ylamino)-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(Indan-2-ylamino)-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(6-Fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(6-Chloro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(6,8-Dichloro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(5,7-Dimethyl-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(1,2,3,4-Tetrahydro-naphthalen-2-ylamino)-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(6-Isopropyl-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-[2-(2-Fluoro-phenyl)-1-methyl-ethylamino]-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-[1-Methyl-2-(3-trifluoromethyl-phenyl)-ethylamino]-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(6-Bromo-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-ethylamino]-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-1-methyl-ethylamino]-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid [1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide;-   2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid    [1-(1,1-dimethyl-3-morpholin-4-yl-propyl)-1H-imidazol-4-yl]-amide;-   2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid    [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        {1-[1,1-dimethyl-2-(1-phenyl-ethylamino)-ethyl]-1H-imidazol-4-yl}-amide;-   2-(6,8-Dichloro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid    [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-4-methyl-pentanoic    acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-N-[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-propionamide;-   2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid    [1-(2-dimethylamino-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide;-   4-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoylamino]-imidazol-1-yl}-benzoic    acid methyl ester;-   2-(6,8-Difluoro-1,1-dimethyl-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(6-Isopropyl-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid [1-(2-hydroxy-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(2-hydroxy-ethyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(2-hydroxy-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(3-hydroxy-1,1-dimethyl-propyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    (1-piperidin-4-yl-1H-imidazol-4-yl)-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(1-methyl-piperidin-4-yl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(1-acetyl-piperidin-4-yl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    (1-piperidin-4-yl-1H-imidazol-4-yl)-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    {1-[1-(3,3-dimethyl-butyryl)-piperidin-4-yl]-1H-imidazol-4-yl}-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    {1-[1-(3,3-dimethyl-butyl)-piperidin-4-yl]-1H-imidazol-4-yl}-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    {1-[1-(2,2-dimethyl-propyl)-piperidin-4-yl]-1H-imidazol-4-yl}-amide;-   2-[6-(4-Fluoro-phenyl)-1,2,3,4-tetrahydro-naphthalen-2-ylamino]-pentanoic    acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-[(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-methyl-amino]-pentanoic    acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [7-(2,2-dimethyl-propyl)-5,5-dimethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-1-yl]-amide;-   2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid    {1-[2-(2,2-dimethyl-propylamino)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-amide;-   2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid    [1-(1,1-dimethyl-2-piperidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid    [1-(2-dimethylamino-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid    {1-[1,1-dimethyl-2-(2,2,2-trifluoro-ethylamino)-ethyl]-1H-imidazol-4-yl}-amide;-   2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid [1-(3-hydroxy-cyclobutyl)-1H-imidazol-4-yl]-amide;-   2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid    {1-[2-(2,6-dimethyl-morpholin-4-yl)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-amide;-   2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid    (1-{2-[(2,2-dimethyl-propyl)-methyl-amino]-1,1-dimethyl-ethyl}-1H-imidazol-4-yl)-amide;-   2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid    {1-[1,1-dimethyl-2-(4-methyl-piperazin-1-yl)-ethyl]-1H-imidazol-4-yl}-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    {1-[2-(2,2-dimethyl-propylamino)-ethyl]-1H-imidazol-4-yl}-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    {1-[2-(4-methyl-piperazin-1-yl)-ethyl]-1H-imidazol-4-yl}-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(2-hydroxy-1,1,2-trimethyl-propyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(3-hydroxy-1,1,3-trimethyl-butyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(2-ethyl-2-hydroxy-1,1-dimethyl-butyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(3-ethyl-3-hydroxy-1,1-dimethyl-pentyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    (1-tert-butyl-1H-imidazol-4-yl)-amide;-   2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid    (1-tert-butyl-1H-imidazol-4-yl)-amide;-   2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid    (1-tert-butyl-1H-imidazol-4-yl)-amide;-   2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid (1-tert-butyl-1H-imidazol-4-yl)-amide;-   2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-N-(1-isopropyl-1H-imidazol-4-yl)-propionamide;-   2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid    (1-isopropyl-1H-imidazol-4-yl)-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    {1-[2-(3-hydroxy-pyrrolidin-1-yl)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    {1-[1-(2,2-dimethyl-propyl)-azetidin-3-yl]-1H-imidazol-4-yl}-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    {1-[1-(2,2-dimethyl-propionyl)-azetidin-3-yl]-1H-imidazol-4-yl}-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(2-isopropoxy-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(6,8-Difluoro-1,2,3,4-tetrahydro-1,4-methano-naphthalen-2-ylamino)-pentanoic    acid    [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(5,7-Difluoro-chroman-3-ylamino)-pentanoic acid    [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(4,6-Difluoro-tricyclo[6.2.2]dodeca-2(7),3,5-trien-9-ylamino)-pentanoic    acid    [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(Naphthalen-2-ylamino)-pentanoic acid    [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(Quinolin-3-ylamino)-pentanoic acid    [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(1-Methyl-1H-indol-3-ylamino)-pentanoic acid    [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-2-trifluoromethyl-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-2-fluoro-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-2-phenyl-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-5-phenyl-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-5-trifluoromethyl-1H-imidazol-4-yl]-amide;-   5-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-3-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-3H-imidazole-4-carboxylic    acid methyl ester;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    (6,6-dimethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-1-yl)-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    (6-methyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    (3,4-dihydro-2H-imidazo[5,1 b][1,3]oxazin-8-yl)-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    (1H-imidazo[1,2-a]pyridin-3-yl)-amide;-   2-[2-(3,5-Difluoro-phenyl)-ethylamino]-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-ethylamino]-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-1-methyl-ethylamino]-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(3,5-Difluoro-benzylamino)-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid [1-(1-dimethylaminomethyl-cyclopentyl)-1H-imidazol-4-yl]-amide;    and-   2-(6,8-Difluoro-1-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide.

Compounds of the Formula I of this invention, and their pharmaceuticallyacceptable salts, have useful pharmaceutical and medicinal properties.The compounds of Formula I, and their pharmaceutically acceptable saltsinhibit the production of Aβ-peptide (thus, gamma-secretase activity) inmammals, including humans. Compounds of the Formula I, and theirpharmaceutically acceptable salts, are therefore able to function astherapeutic agents in the treatment of the neurodegenerative and/orneurological disorders and diseases representatively enumerated below,for example Alzheimer's disease, in an afflicted mammal, including ahuman.

The present invention also relates to a pharmaceutical composition forinhibiting Aβ-peptide production in a mammal, including a human,comprising an amount of a compound of the Formula I, or apharmaceutically acceptable salt thereof, that is effective ininhibiting Aβ-production, and a pharmaceutically acceptable carrier.

The present invention also relates to a pharmaceutical composition fortreating a disease or condition selected from the group consisting ofAlzheimer's disease, hereditary cerebral hemorrhage with amyloidosis,cerebral amyloid angiopathy, a prion-mediated disease, inclusion bodymyositis, stroke, multiple sclerosis, head trauma, mild cognitiveimpairment and Down's Syndrome in a mammal, including a human,comprising an amount of a compound of the Formula I, or apharmaceutically acceptable salt thereof, that is effective ininhibiting Aβ-peptide production, and a pharmaceutically acceptablecarrier.

The present invention also relates to a pharmaceutical composition fortreating a disease or condition selected from the group consisting ofAlzheimer's disease and Down's Syndrome in a mammal, including a human,comprising an amount of a compound of the Formula I, or apharmaceutically acceptable salt thereof, that is effective ininhibiting Aβ-peptide production, and a pharmaceutically acceptablecarrier.

The present invention also relates to a pharmaceutical composition fortreating a disease or a condition selected from the group consisting ofAlzheimer's disease, hereditary cerebral hemorrhage with amyloidosis,cerebral amyloid angiopathy, a prion-mediated disease, inclusion bodymyositis, stroke, multiple sclerosis, head trauma, mild cognitiveimpairment and Down's Syndrome in a mammal, including a human,comprising an amount of a compound of the Formula I, or apharmaceutically acceptable salt thereof, that is effective in treatingsuch disease or condition, and a pharmaceutically acceptable carrier.

The present invention also relates to a pharmaceutical composition fortreating a disease or a condition selected from the group consisting ofAlzheimer's disease and Down's Syndrome in a mammal, including a human,comprising an amount of a compound of the Formula I, or apharmaceutically acceptable salt thereof, that is effective in treatingsuch disease or condition, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of inhibiting Aβ-peptideproduction in a mammal, including a human, comprising administering tosaid mammal an amount of a compound of the Formula I, or apharmaceutically acceptable salt thereof, that is effective ininhibiting Aβ-production.

The present invention also relates to a method of treating a disease orcondition selected from Alzheimer's disease, hereditary cerebralhemorrhage with amyloidosis, cerebral amyloid angiopathy, aprion-mediated disease, inclusion body myositis, stroke, multiplesclerosis, head trauma, mild cognitive impairment and Down's Syndrome ina mammal, including a human, comprising administering to said mammal anamount of a compound of the Formula I, or a pharmaceutically acceptablesalt thereof, that is effective in inhibiting Aβ-production.

The present invention also relates to a method of treating a disease orcondition selected from Alzheimer's disease and Down's Syndrome in amammal, including a human, comprising administering to said mammal anamount of a compound of the Formula I, or a pharmaceutically acceptablesalt thereof, that is effective in inhibiting Aβ-production.

The present invention also relates to a method of treating a disease orcondition selected from Alzheimer's disease, hereditary cerebralhemorrhage with amyloidosis, cerebral amyloid angiopathy, aprion-mediated disease, inclusion body myositis, stroke, multiplesclerosis, head trauma, mild cognitive impairment and Down's Syndrome ina mammal, including a human, comprising administering to said mammal anamount of a compound of the Formula I, or a pharmaceutically acceptablesalt thereof, that is effective in treating such condition.

The present invention also relates to a method of treating a disease orcondition selected from Alzheimer's disease and Down's Syndrome in amammal, including a human, comprising administering to said mammal anamount of a compound of the Formula I, or a, pharmaceutically acceptablesalt thereof, that is effective in treating such condition.

The compounds of Formula I may be used alone or used in combination withany other drug, including, but not limited to, any memory enhancementagent, e.g., Aricept™ and/or Namenda™, antidepressant agent, e.g.,Zoloft™, anxiolytic, antipsychotic agent, e.g., Geodon™, sleep disorderagent, anti-inflammatory agent, e.g., Celebrex™, Bextra™, etc.,anti-oxidant agent, cholesterol modulating agent (for example, an agentthat lowers LDL or increases HDL), e.g., Lipitor™, Caduet™, etc.,Histamine (H2) antagonist, e.g., Cimetadine™, and anti-hypertensionagent, e.g., Norvasc™, Caduet™, etc. Accordingly, the present inventionalso relates to the following pharmaceutical compositions and methods oftreatment comprising a compound of the Formula I in combination withother drugs, such as those of the type described above.

The present invention also relates to a pharmaceutical composition fortreating a disease or condition associated with Aβ-peptide production ina mammal, including a human, comprising (a) a compound of the Formula I,or a pharmaceutically acceptable salt thereof; (b) a memory enhancementagent, e.g., Aricept™ and/or Namenda™, antidepressant, e.g., Zoloft™,anxiolytic, antipsychotic agent, e.g., Geodon™, sleep disorder agent,anti-inflammatory agent, e.g., Celebrex™, Bextra™, etc., anti-oxidantagent, cholesterol modulating agent (for example, an agent that lowersLDL or increases HDL), e.g., Lipitor™, Caduet™, etc., Histamine (H2)antagonist, e.g., Cimetadine™, and anti-hypertensive agent, e.g.,Norvasc™, Caduet™, etc.; and (c) a pharmaceutically acceptable carrier;wherein the active agents “a” and “b” above are present in amounts thatrender the composition effective in treating such disease or condition.

The present invention also relates to a pharmaceutical composition fortreating a disease or condition selected from the group consisting ofAlzheimer's disease, hereditary cerebral hemorrhage with amyloidosis,cerebral amyloid angiopathy, a prion-mediated disease, inclusion bodymyositis, stroke, multiple sclerosis, head trauma, mild cognitiveimpairment and Down's Syndrome, in a mammal, including a human,comprising (a) a compound of the Formula I, or a pharmaceuticallyacceptable salt thereof; (b) a memory enhancement agent, e.g., Aricept™and/or Namenda™, antidepressant, e.g., Zoloft™, anxiolytic,antipsychotic agent, e.g., Geodon™, sleep disorder agent,anti-inflammatory agent, e.g., Celebrex™, Bextra™, etc., anti-oxidantagent, cholesterol modulating agent (for example, an agent that lowersLDL or increases HDL), e.g., Lipitor™, Caduet™, etc., Histamine (H2)antagonist, e.g., Cimetadine™, and anti-hypertensive agent, e.g.,Norvasc™, Caduet™, etc.; and (c) a pharmaceutically acceptable carrier;wherein the active agents “a” and “b” above are present in amounts thatrender the composition effective in treating such disease or condition.

The present invention also relates to a pharmaceutical composition fortreating a disease or condition selected from the group consisting ofAlzheimer's disease and Down's Syndrome, in a mammal, including a human,comprising (a) a compound of the Formula I, or a pharmaceuticallyacceptable salt thereof; (b) a memory enhancement agent, e.g., Aricept™and/or Namenda™, antidepressant, e.g., Zoloft™, anxiolytic,antipsychotic agent, e.g., Geodon™, sleep disorder agent,anti-inflammatory agent, e.g., Celebrex™, Bextra™, etc., anti-oxidantagent, cholesterol modulating agent (for example, an agent that lowersLDL or increases HDL), e.g., Lipitor™, Caduet™, etc., Histamine (H2)antagonist, e.g., CimetadineM, and anti-hypertensive agent, e.g.,Norvasc™, Caduet™, etc.; and (c) a pharmaceutically acceptable carrier;wherein the active agents “a” and “b” above are present in amounts thatrender the composition effective in treating such disease or condition.

The present invention also relates to a method of treating a disease orcondition associated with Aβ-peptide production in a mammal, including ahuman, comprising administering to said mammal (a) a compound of theFormula I, or a pharmaceutically acceptable salt thereof; and (b) amemory enhancement agent, e.g., Aricept™ and/or Namenda™,antidepressant, e.g., Zoloft™, anxiolytic, antipsychotic agent, e.g.,Geodon™, sleep disorder agent, anti-inflammatory agent, e.g., Celebrex™,Bextra™, etc., anti-oxidant agent, cholesterol modulating agent (forexample, an agent that lowers LDL or-increases HDL), e.g., Lipitor™,Caduet™, etc., Histamine (H2) antagonist, e.g., Cimetadine™, andanti-hypertensive agent, e.g., Norvasc™, Caduetim, etc.; wherein theactive agents “a” and “b” above are present in amounts that render thecomposition effective in treating such disease or condition.

The present invention also relates to a method of treating a disease orcondition selected from the group consisting of Alzheimer's disease,hereditary cerebral hemorrhage with amyloidosis, cerebral amyloidangiopathy, a prion-mediated disease, inclusion body myositis, stroke,multiple sclerosis, head trauma, mild cognitive impairment and Down'sSyndrome, in a mammal, including a human, comprising administering tosaid mammal (a) a compound of the Formula I, or a pharmaceuticallyacceptable salt thereof; and (b) a memory enhancement agent, e.g.,Aricept™ and/or Namenda™, antidepressant, e.g., Zoloft™, anxiolytic,antipsychotic agent, e.g., Geodon™, sleep disorder agent,anti-inflammatory agent, e.g., Celebrex™, Bextra™, etc., anti-oxidantagent, cholesterol modulating agent (for example, an agent that lowersLDL or increases HDL), e.g., Lipitor™, Caduet™, etc., Histamine (H2)antagonist, e.g., Cimetadine™, and anti-hypertensive agent, e.g.,Norvasc™, Caduet™, etc.; wherein the active agents “a” and “b” above arepresent in amounts that render the composition effective in treatingsuch disease or condition.

The present invention also relates to a method of treating a disease orcondition selected from the group consisting of Alzheimer's disease andDown's Syndrome, in a mammal, including a human, comprisingadministering to said mammal (a) a compound of the Formula I, or apharmaceutically acceptable salt thereof; and (b) a memory enhancementagent, e.g., Aricept™ and/or Namenda™, antidepressant, e.g., Zoloft™,anxiolytic, antipsychotic agent, e.g., Geodon™, sleep disorder agent,anti-inflammatory agent, e.g., Celebrex™, Bextra™, etc., anti-oxidantagent, cholesterol modulating agent (for example, an agent that lowersLDL or increases HDL), e.g., Lipitor™, Caduet™, etc., Histamine (H2)antagonist, e.g., Cimetadine™, and anti-hypertensive agent, e.g.,Novasc™; Caduet™, etc.; wherein the active agents “a” and “b” above arepresent in amounts that render the composition effective in treatingsuch disease or condition.

Compounds of the Formula I, or any of the combinations described in theimmediately preceding paragraphs, may optionally be used in conjunctionwith a known P-glycoprotein inhibitor, such as verapamil.

References herein to diseases and conditions “associated with Aβ-peptideproduction” relate to diseases or conditions that are caused, at leastin part, by AD-peptide and/or the production thereof. Thus, Aβ-peptideis a contributing factor, but not necessarily the only contributingfactor, to “a disease or condition associated with Aβ-peptideproduction.”

The compounds of Formula I, or their pharmaceutically acceptable saltsmay also be used to modulate or inhibit the Notch signaling pathway inorganisms, including humans. The Notch signaling pathway is anevolutionarily conserved mechanism utilized by organisms, ranging fromworms through humans, to regulate fate determination of various celllineages. Notch belongs to the family of epidermal growth factor-likehomeotic genes, which encode transmembrane proteins with variablenumbers of epidermal growth factor-like repeats in the extracellulardomain. There is increasing evidence for a role of the Notch pathway inhuman disease. All of the components of the pathway have yet to beidentified, but among those identified to date, mutations that affecttheir interaction with each other can lead to a variety of syndromes andpathological conditions.

For example, Notch signaling is typically associated with cell fatedecision. The finding that Notch activation stimulates capillaryoutgrowth suggests that Notch receptors must be activated to allow thisprocess to occur. Therefore, Notch modulation provides a method forregulating angiogenesis. Specifically, modulation of Notch signaling canbe used to modulate angiogenesis (e.g., by blocking Notch signaling toblock angiogenesis). This inhibition of angiogenesis in vivo can be usedas a therapeutic means to treat a variety of diseases, including but notlimited to cancer, diabetic retinopathy, rheumatoid arthritis,psoriasis, inflammatory bowel disease and arteriosclerosis.

The Notch pathway is also implicated in the development and maturationof T cells, as described in Radtke, F. et al., Immunity 10:547-558,1999. The compounds of Formula I, and their pharmaceutically acceptablesalts are therefore useful candidates for modulating the immune system,including the treatment of inflamamation, asthma, graft rejection, graftversus host disease, autoimmune disease and transplant rejection.

In addition, a number of studies published between 2002 and 2004 haveprovided convincing evidence that Notch signaling is frequently elevatedin a variety of human tumors (including, but not limited to breast,prostate, pancreas and T-cell acute lymphoblastic leukemia). One keystudy provides a strong genetic link to Notch's role in important tumortypes. Specifically, Weijzen et al. demonstrated that Notch signalingmaintains the neoplastic phenotype in human Ras-transformed cells.Weijzen et al. (2002) Nature Med 8: 979. Because 30% of humanmalignancies may carry activating mutations in at least one of the threeisoforms of Ras, this finding raises the possibility that Notchinhibitors would be a powerful addition to anti-cancer therapy. Anotherstudy's findings support a central role for aberrant Notch signaling inthe pathogenesis of human T cell acute lymphoblastic leukemia/lymphoma.Pear et al., Current Opinion in Hematology (2004), 11(6), 426-433.

Accordingly, the compounds of Formula I, or their pharmaceuticallyacceptable salts, may be used for treating a disease or conditionselected from the group consisting of cancer, arteriosclerosis, diabeticretinopathy, rheumatoid arthritis, psoriasis, inflammatory bowel diseaseinflammation, asthma, graft rejection, graft versus host disease,autoimmune disease and transplant rejection.

As used herein, the term “treating” refers to reversing, alleviating orinhibiting the progress of a disease, disorder or condition, or one ormore symptoms of such disease, disorder or condition, to which such termapplies. As used herein, “treating” may also refer to decreasing theprobability or incidence of the occurrence of a disease, disorder orcondition in a mammal as compared to an untreated control population, oras compared to the same mammal prior to treatment. For example, as usedherein, “treating” may refer to preventing a disease, disorder orcondition, and may include delaying or preventing the onset of adisease, disorder or condition, or delaying or preventing the symptomsassociated with a disease, disorder or condition. As used herein,“treating” may also refer to reducing the severity of a disease,disorder or condition or symptoms associated with such disease, disorderor condition prior to a mammal's affliction with the disease, disorderor condition. Such prevention or reduction of the severity of a disease,disorder or condition prior to affliction relates to the administrationof the composition of the present invention, as described herein, to asubject that is not at the time of administration afflicted with thedisease, disorder or condition. As used herein “treating” may also referto preventing the recurrence of a disease, disorder or condition or ofone or more symptoms associated with such disease, disorder orcondition. The terms “treatment” and “therapeutically,” as used herein,refer to the act of treating, as “treating” is defined above.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of the Formula I, and their pharmaceutically acceptable salts,may be prepared as described in the following reaction Schemes anddiscussion. Unless otherwise indicated, as referred to in the reactionschemes and discussion that follow, R¹, R², R³, R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰,R¹¹, A, Z and n are as defined above.

The compounds of Formula I may have asymmetric carbon atoms and maytherefore exist as racemic mixtures, diasteroisomers, or as individualoptical isomers.

Separation of a mixture of isomers of compounds of Formula I into singleisomers may be accomplished according to conventional methods known inthe art.

The compounds of the Formula I may be prepared by the methods describedbelow, together with synthetic methods known in the art of organicchemistry, or modifications and derivatisations that are familiar tothose of ordinary skill in the art. Preferred methods include, but arenot limited to, those described below.

The reactions described below are performed in solvents that areappropriate to the reagents and materials employed and that are suitablefor use in the reactions described. In the description of the syntheticmethods described below, it is also to be understood that all reactionconditions, whether actual or proposed, including choice of solvent,reaction temperature, reaction duration time, reaction pressure, andother reaction conditions (such as anhydrous conditions, under argon,under nitrogen, etc.), and work up procedures, are those conditions thatare standard for that reaction, as would be readily recognized by one ofskill in the art. Alternate methods may also be used.

Compounds of formula II wherein R⁷ contains an alcohol moiety may beoxidized using standard oxidation method known in art, such as, e.g.,Dess-Martin reagents, Swern oxidation, or use of SO₃-pyridine, CrO₃, toprovide compounds of formula II wherein R⁷ contains a ketone oraldehyde. Compounds of formula II wherein R⁷ is a ketone or aldehyde mayconvert to the corresponding compounds of formula II wherein R⁷ is animine (by reaction with an amine), olefin (by a Wittig reaction),alcohol (by a Grignard reaction), or other derivative (by standardreactions).

The compounds of formula I of the present invention and their salts canbe prepared by a reaction process comprising a compound of formula II

with a compound of formula III

or reacting a compound of formula IV

-   -   with a compound of formula V    -   wherein R², R³, R⁴, R⁶, R⁷, and A are as defined above and L is        hydroxy or a suitable leaving group. If desired, the        4-amino-imidazole derivative of formula I or synthetic        intermediate of formula IV may be converted into a salt by        methods known to those of ordinary skill in the art.

Examples of specific compounds of formula III and V wherein L is hydroxyor a suitable leaving group are those wherein L represents a halogenatom, such as Cl, Br, or I, or A-L is an alkyl or aryl ester.

Compounds in formula I can be prepared by reacting a compound of formulaII and a carboxylic acid of formula III, or a compound of formula IVwith a compound of formula V. Compounds of formula IV can be prepared byreacting a compound of formula II with a compound of formula VI.

The reaction between compounds of formula II and compounds of formulaIII, between compounds of formula IV and compounds of formula V, andbetween compounds of formula II and compounds of formula VI, can becarried out by standard methods. For example, wherein L is a hydroxygroup, these reactions can be carried out in the presence of a couplingagent or a polymer supported coupling agent, such as, for example,carbodiimide, i.e. 1,3-dicyclohexylcarbodiimide (DCC),1,3-diisopropylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC),N-cyclohexylcarbodiimide, or N′-methylpolystyrene in the presence orabsence of HOBt, in a suitable solvent such as, for instance, a singlesolvent or a combination of several solvents selected fromdichloromethane (CH₂Cl₂), chloroform (CHCl₃), tetrahydrofuran (THF),diethyl ether (Et₂O), 1,4-dioxane, acetonitrile, (CH₃CN), toluene,N,N-dimethylformamide (DMF), or dimethylsulfoxide (DMSO), at a suitabletemperature such as from about −10° C. to about reflux, for a suitabletime monitored by chromatography or LC-MS. An alternative method whereinL is OH is carried out by converting OH to a leaving group by reactionwith oxalyl chloride, thionyl chloride or a mixed anhydride method,using an alkyl chloroformate, such as C₁-C₄ alkyl chloroformate, in thepresence of a base such as triethylamine, N,N-diisopropylethylamine,pyridine, or dimethylaminopyridine, in a suitable solvent such as, forexample, methylene chloride, chloroform, tetrahydrofuran (THF), toluene,diethyl ether, acetonitrile, 1,4-dioxane, n,N-dimethylformamide,dimethylsulfoxide (DMSO), N-methylpyrrolidinone (NMP), or xylene, at atemperature of from about −30° C. to about room temperature.

Alternatively, aminoimidazole coupling may be achieved as follows. Acompound of formula I may be prepared by coupling an amino-imidazole 11with III wherein C(═O)L is an ester, in the presence oftrialkylaluminium preferably trimethylaluminum in an appropriate solventsuch as methylene chloride, THF, dioxane, toluene, etc., at anappropriate temperature, such as from about room temperature to aboutreflux, or in a sealed reactor (such as sealed tube or inscrewed vials).Similarly, compound IV may be prepared by reacting an amino-imidazoleII, triamethylaluminum and N-Boc of an alpha-amino acid ester, followedby removal of the Boc group using standard methods.

The protected amino compounds of formula VI, where P¹ is a blockinggroup such as an N-Boc group, can be prepared by methods well known inthe literature, for example the methods described in Theodora W.Greene's book “Protective Groups in Organic Synthesis”. Compounds offormula IV can be prepared in an analogous method as above by reactingcompound of formula II with a compound of formula VI, followed bydeblocking the P¹ group. Deprotection can be performed by well-knownmethods, for example when P¹ is N-Boc, removal by any methods well-knownin the literature, for example HCl(g) in an appropriate solvent such as1,4-dioxane, diethylether or trifluoroacetic acid in methylene chloride.Many other amino protecting groups are known and may also be used, suchas benzyl or p methoxy-benzyl, trimethylsilyl, t-butyldimethylsilyl,etc. Methods for deblocking such groups are also well-known in theliterature and may be used.

The compounds of formula II, III, IV, V and VI, in certaincircumstances, are known compounds or can be obtained according tomethods well known to one of skill in the art.

Compounds of formula III and V, wherein L is a leaving group as definedabove, can be obtained according to conventional methods from thecorresponding carboxylic acids of formula III where X is hydroxy.

Compounds of formula IV can be prepared by reacting a compound offormula II with a compound of formula V using known methods.

An ester group of R⁷ in compounds of formula I or II may be converted tothe corresponding amide using a similar method for amide bond formation,preferably employing trimethylaluminum in an appropriate solvent or amixture of solvents, such as THF/toluene.

A keto group of R⁷ in compounds of formula I or II may be converted tothe corresponding amine using a well-established reductive aminationmethod by reacting such ketone with an appropriate amine, with orwithout acid catalyst/ammonium acetate/dry agents (such as anhydrousNa₂SO₄ or MgSO₄), and a reducing agent, such as sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride, or thecorresponding polymer bound-NaBH₄, polymer bound-NaBH₃CN, or polymerbound-NaB(OAc)₃H, or any reducing agent (e.g., hydrogenation) that isknown in the literature for reducing an imine bond to an amine, in anappropriate solvent, such as dichloroethane, chloroform, THF, MeOH,ethanol, isopropanol, t-butanol or toluene, at a temperature from aboutroom temperature to about reflux, preferably from about room temperatureto about 65° C.

Compounds wherein R⁶ is a halo group may be generated by reacting thestarting material wherein R⁶ is H with NBS (N-bromosuccinamide),NCS(N-chlorosuccinamide), or SO₂Cl₂, I₂ in an appropriate solvent suchas methylene chloride, carbontetrachloride or chloroform. The halo groupmay then be replaced with another group using methods known in the art,such as halogen-metal exchange, followed by quenching with anelectrophile, or using typical Suzuki coupling conditions employing acatalyst such as a palladium complex, e.g.,tetrakis(triphenylphosphine)-palladium, with sodium carbonate as a base,in a suitable solvent such as THF, DME, or ethanol, and a boronic acid.

4-amino-imidazole II may be prepared by the following methods known inthe chemical literature (e.g., Tetrahedron, 1995, 51, 2875-2894; J.Chem. Soc. Perkin 1, 1987, 2819-2828; Bull. Chem. Soc. Fr. 1994, 131,200-209; Tetrahedron Lett. 1996, 4423-4426; Tetrahedron 1996, 37,4423-4426; Tetrahedron, 1994, 50, 5741-5752; Heterocycles, 1994, 37,1511-1520; Tetrahedron Lett. 1999, 1623-1626; Organic Lett. 2002, 4,4133-4134; Organic Lett. 2000, 2, 1233-1236; J. Med. Chem. 1990, 33,1091-1097; or by the methods described below.

Scheme 1 illustrates methods suitable for preparing amino-imidazolecompounds of formula I. Referring to Scheme 1, treatment of a solutionof 1,4-dinitroimidazole (J. Phys. Chem. (1995) Vol. 99, pp. 5009-5015)in dimethylsulfoxide (DMSO), pyridine-water, water, an alcohol, or analcohol-water solvent system, but preferably in a lower alcohol such asmethanol, from about −20° C. to about 50° C., preferably from about −5°C. to 35° C., with a primary alkyl or aryl amine (NR⁹R¹⁰) affords1-N-substituted-4-nitroimidazoles of formula 2A. 1,4-dinitroimidazole isa highly energetic, semi-stable substance and should be stored in afreezer at all times it is not in use. Thermodynamic measurements haveshown that it can potentially generate enough energy at 35° C. underadiabatic conditions to violently explode. Extreme caution should beexercised at all time using this material. Reduction of the nitrocompound of formula 2A to the amine of formula 3A may be accomplished byexposing a mixture of a compound of formula 2A and a noble metalcatalyst, in a solvent such as ethyl acetate, tetrahydrofuran, dioxane,or a mixture thereof, to an atmosphere of hydrogen gas at a pressure ofabout 1 to 100 atmospheres, where a preferred pressure of hygrogen gasis about one to about ten atmospheres. Palladium is the preferred noblemetal catalyst. The metal may be conveniently suspended on an inertsolid support such as charcoal and filtered to provide the amine offormula 3A. Alternatively, the nitro group of formula 2A to the amine offormula 3A may be accomplished by exposing a mixture of a compound offormula 2A to zinc/HCl or iron/HCl or with NaBH₄/NiCl₂ or with NaBH₂S₃:

The resulting amine of formula 3A is reacted immediately with an acidchloride, acid anhydride, or an activated carboxylic acid derivative(defined by Formula II), in the presence of a base, such astriethylamine, diisopropylethylamine, pyridine, or 2,6-lutidine, fromabout −78° C. to 40° C. The reaction between compounds of formula 3A andcompounds of formula III can be carried out by standard methods. Forexample, wherein L of formula III is a hydroxy group, these reactionscan be carried out in the presence of a coupling agent or a polymersupported coupling agent, such as, for example, carbodiimide, i.e.1,3-dicyclohexylcarbodiimide (DCC), 1,3-diisopropylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC),N-cyclohexylcarbodiimide, or N′-methylpolystyrene in the presence orabsence of HOBt, in a suitable solvent such as, for instance, a singlesolvent or a combination of several solvents selected fromdichloromethane (CH₂Cl₂), chloroform (CHCl₃), tetrahydrofuran (THF),diethyl ether (Et₂O), 1,4-dioxane, acetonitrile, (CH₃CN), toluene,N,N-dimethylformamide (DMF), or dimethylsulfoxide (DMSO), at a suitabletemperature such as from about −10° C. to about reflux, for a suitabletime monitored by chromatography or LC-MS. An alternative method whereinL is OH is carried out by converting OH to a leaving group by reactionwith oxalyl chloride, thionyl chloride or a mixed anhydride method,using an alkyl chloroformate, such as C₁-C₄ alkyl chloroformate, in thepresence of a base such as triethylamine, N,N-diisopropylethylamine,pyridine, or dimethylaminopyridine, in a suitable solvent such as, forexample, methylene chloride, chloroform, tetrahydrofuran (THF), toluene,diethyl ether, acetonitrile, 1,4-dioxane, N,N-dimethylformamide,dimethylsulfoxide (DMSO), N-methylpyrrolidinone (NMP), or xylene, at atemperature of from about −30° C. to about room temperature.

Alternatively, aminoimidazole coupling may be achieved as follows. Acompound of formula I may be prepared by coupling an amino-imidazole 3Awith a compound of formula III wherein C(═O)L is an ester, in thepresence of trialkylaluminium preferably trimethylaluminum in anappropriate solvent such as methylene chloride, THF, dioxane, toluene,etc., at an appropriate temperature, such as from about room temperatureto about reflux, or in a sealed reactor (such as sealed tube orinscrewed vials).

Alternatively, the resulting amine of formula 3A is reacted immediatelywith an acid chloride, acid anhydride, or an activated carboxylic acidderivative (defined by Formula IV), in the presence of a base, such astriethylamine, diisopropylethylamine, pyridine, or 2,6-lutidine, fromabout −78° C. to 40° C. to form a compound of formula 4A. The reactionbetween compounds of formula 3A and compounds of formula IV can becarried out by standard methods. For example, wherein L of formula IV isa hydroxy group, these reactions can be carried out in the presence of acoupling agent or a polymer supported coupling agent, such as, forexample, carbodiimide, i.e. 1,3-dicyclohexylcarbodiimide (DCC),1,3-diisopropylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC),N-cyclohexylcarbodiimide, or N′-methylpolystyrene in the presence orabsence of HOBt, in a suitable solvent such as, for instance, a singlesolvent or a combination of several solvents selected fromdichloromethane (CH₂Cl₂), chloroform (CHCl₃), tetrahydrofuran (THF),diethyl ether (Et₂O), 1,4-dioxane, acetonitrile, (CH₃CN), toluene,N,N-dimethylformamide (DMF), or dimethylsulfoxide (DMSO), at a suitabletemperature such as from about −10° C. to about reflux, for a suitabletime monitored by chromatography or LC-MS. An alternative method whereinL is OH is carried out by converting OH to a leaving group by reactionwith oxalyl chloride, thionyl chloride or a mixed anhydride method,using an alkyl chloroformate, such as C₁-C₄ alkyl chloroformate, in thepresence of a base such as triethylamine, N,N-diisopropylethylamine,pyridine, or dimethylaminopyridine, in a suitable solvent such as, forexample, methylene chloride, chloroform, tetrahydrofuran (THF), toluene,diethyl ether, acetonitrile, 1,4-dioxane, N,N-dimethylformamide,dimethylsulfoxide (DMSO), N-methyl pyrrolidinone (NMP), or xylene, at atemperature of from about −30° C. to about room temperature.

Alternatively, aminoimidazole coupling may be achieved as follows. Acompound of formula 4A may be prepared by coupling an amino-imidazole 3Awith a compound of formula IV wherein C(═O)L is an ester, in thepresence of trialkylaluminium preferably trimethylaluminum in anappropriate solvent such as methylene chloride, THF, dioxane, toluene,etc., at an appropriate temperature, such as from about room temperatureto about reflux, or in a sealed reactor (such as sealed tube orinscrewed vials). The protected amino compounds defined as PG, such as acompound with an Boc group, of formula IV can be prepared by methodswell known in the literature, for example the methods described inTheodora W. Greene's book “Protective Groups in Organic Synthesis”.

Compounds defined as by Formula 5A can be prepared from compounds offormula 4A by deblocking the PG group. Deprotection can be performed bywell-known methods, for example when PG is N-Boc, removal by any methodswell-known in the literature, for example HCl(g) in an appropriatesolvent such as 1,4-dioxane, diethylether or trifluoroacetic acid inmethylene chloride. Many other amino protecting groups are known and mayalso be used, such as benzyl or p-methoxy-benzyl, trimethylsilyl,t-butyidimethylsilyl, etc. Methods for deblocking such groups are alsowell-known in the literature and may be used.

Compounds of the Formula I can be formed by reaction between compoundsof formula 5A and compounds of formula V can be carried out by standardmethods. For example, wherein L is a hydroxy group, these reactions canbe carried out in the presence of a coupling agent or a polymersupported coupling agent, such as, for example, carbodiimide, i.e.1,3-dicyclohexylcarbodiimide (DCC), 1,3-diisopropylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC),N-cyclohexylcarbodiimide, or N′-methylpolystyrene in the presence orabsence of HOBt, in a suitable solvent such as, for instance, a singlesolvent or a combination of several solvents selected fromdichloromethane (CH₂Cl₂), chloroform (CHCl₃), tetrahydrofuran (THF),diethyl ether (Et₂O), 1,4-dioxane, acetonitrile, (CH₃CN), toluene,N,N-dimethylformamide (DMF), or dimethylsulfoxide (DMSO), at a suitabletemperature such as from about −10° C. to about reflux, for a suitabletime monitored by chromatography or LC-MS. An alternative method whereinL is OH is carried out by converting OH to a leaving group by reactionwith oxalyl chloride, thionyl chloride or a mixed anhydride method,using an alkyl chloroformate, such as C₁-C₄ alkyl chloroformate, in thepresence of a base such as triethylamine, N,N-diisopropylethylamine,pyridine, or dimethylaminopyridine, in a suitable solvent such as, forexample, methylene chloride, chloroform, tetrahydrofuran (THF), toluene,diethyl ether, acetonitrile, 1,4-dioxane, n,N-dimethylformamide,dimethylsulfoxide (DMSO), N-methylpyrrolidinone (NMP), or xylene, at atemperature of from about −30° C. to about room temperature.

Alternatively, aminoimidazole coupling may be achieved as follows. Acompound of formula I may be prepared by coupling an amino-imidazole 5Awith V wherein L is an ester, in the presence of trialkylaluminiumpreferably trimethylaluminum in an appropriate solvent such as methylenechloride, THF, dioxane, toluene, etc., at an appropriate temperature,such as from about room temperature to about reflux, or in a sealedreactor (such as sealed tube or inscrewed vials).

Alternatively, compounds of the Formula I can be formed by reactionbetween compounds of formula 5A and compounds of formula V when L is analdehyde or ketone by using a well-established reductive aminationmethod by reacting such ketone or aldehyde with an appropriate amine 5A,with or without acid catalyst/ammonium acetate/dry agents (such asanhydrous Na₂SO₄ or MgSO₄), and a reducing agent, such as sodiumtriacetoxy borohydride, sodium cyanoborohydride, or sodium borohydride,or the corresponding polymer bound-NaBH₄, polymer bound-NaBH₃CN, orpolymer bound-NaB(OAc)₃H, or any reducing agent (e.g., hydrogenation)that is known in the literature for reducing an imine bond to an amine,in an appropriate solvent, such as dichloroethane, chloroform, THF,MeOH, ethanol, isopropanol, t-butanol or toluene, at a temperature fromabout room temperature to about reflux, preferably from about roomtemperature to about 65° C.

Scheme 2 illustrates additional methods for the synthesis of imidazolecompounds defined as Formula 2A. Treatment of nitroimidazole 6A with abase such as sodium hydride, potassium hydride, alkyl lithium,alkoxides, in a solvent such as tetrahydrofuran, dimethylformamide,methylene chloride, ether, preferably dimethylformamide, from about −60°C. to 40° C., where from −10° C. to 20° C. is preferred, followed byaddition of R⁷-X wherein X is defined as Cl, Br, I, F, alkylsulfonate,or arylsulfonate followed by warming the reaction from 23° C. to 150° C.where 30-80° C. is preferrable, affords imidazoles of formula 2A.Reduction of the nitro compound and coupling reaction is carried out ina similar manner described above and is useful for preparing compoundsof the Formula I.

Scheme 3 illustrates additional methods for the synthesis ofnitro-imidazole compounds defined as Formula 2A. A key starting materialfor the synthesis is the double-bond compound (a compound of Formula 16or 17) substituted with the group ER8 and one to three groups selectedfrom R⁸, where ER8 is defined as an electron-withdrawing group chosenfrom C(═O)R⁹, C(═O)OR⁹, C9=O)NR⁹R¹⁰, S(═O)₂R⁹, S(═O)₂ NR⁹R¹⁰, S(═O)₂OR⁹,cyano, and heteroaryl. Additionally, compounds of formula 16 or 17 maybe defined wherein ER8 is connected to one of the groups R⁸ or directlyto the carbon-carbon double bond to form a ring and thus includescomopunds such as 2-cyclopentene-1-one and 2-cyclohexene-1-one.Alternatively, compounds of formula 17 where L is defined as Cl, Br, I,OC(═O)R⁹, or OS(═O)₂R⁹ may be used as starting materials; examples ofsuch compounds are 3-chloro-1-cyclopentanone, 3-acetoxy-1-cyclobutanone.Thus, referring to Scheme 3, treatment of −=4-nitroimidazole 6A, with abase such as sodium hydride, potassium hydride, cesium carbonate,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or tetraalkylammonium chloride,where DBU is the preferred base, with intermediates 16 or 17 in asolvent such as acetonitrile, methylene chloride, 1,2-dichloroethane, orchloroform, where acetonitrile is the preferred solvent, at atemperature from about 60° C. to about 50° C., where −20° C. to 23° C.is the preferred range, affords addition products of formula 2A.Reduction of the nitro compound and coupling to give compounds offormula I is carried out in a similar manner described above.

Scheme 4 below illustrates additional methods for the synthesis ofamino-imidazole compounds defined as Formula 2A. Treatment ofethyl-2-isocyano-3-N,N-dimethylamino acrylate orbenzyl-2-isocyano-3-N,N-dimethylamino acrylate with a primary amine,R7-NH2, in a solvent such as n-butanol, n-propanol, i-propanol, orethanol, or in the absence of solvent, where n-propanol or no solventare preferred, from about 23° C. to about 200° C., where from about 60°C. to 150° C. is preferred, affords imidazoles of formula 18. Treatmentof ester 18 with a base such as potasium hydroxide, lithium hydroxide,or sodium hydroxide in a—solvent such as tetrahydrofuran, water,methanol, ethanol, propanol, wherein methanol is preferred provides theacid 19. The acid is converted to the acylazide 20 using methods knownto one skilled in the art such as treatment of acid 19 with thionytchloride or oxalyl chloride from −20 to 50° C. followed by removal ofthe residual solvent and quenching with sodium or potassium azide in asolvent such as toluene, tetrahydrofuran, methlene chloride, dioxane.The azide 20 undergoes Curtius rearrangement to the Boc 21 by heatingfrom 5° C.-200° C. in a solvent such as t-butanol, benzyl alcohol, andethanol. If t-butanol is used, deprotection of the N-Boc protectinggroup can be accomplished with HCl or triflouroacetic acid in a solventsuch as ether, tetrahydrofuran, where HCl in methanol is preferredaffords the desired aminoimidazole compounds of formula 2A. If benzylalcohol is used, deprotection can be accomplished by the use of a noblemetal catalyst, in a solvent such as ethyl acetate, tetrahydrofuran,dioxane, or a mixture thereof, to an atmosphere of hydrogen gas at apressure of about 1 to 100 atmospheres, where a preferred pressure ofhygrogen gas is about one to about ten atmospheres. Palladium is thepreferred noble metal catalyst which affords the desired aminoimidazolecompounds of formula 2A. Alternatively, ester 18 can be treated withhydrazine in a solvent such as water from a temperature from 50° C. to200° C. where 80° C. to 120° C. is preferred provides the hydrazide 22.The hydrazide 22 can be converted to the acylazide 20 usingt-butyinitrite in a solvent or combination of solvent such as ether,methylene chloride, dichloroethane, chloroform, where in ether/methylenechloride is preferred at a temperature from −50° C. to 23° C. wherein−30° C. to 10° C. is preferred. The acylazide is then converted ontoaminoimidazole compounds of formula 2A as described above. Made a changeto scheme 4

Scheme 5 below illustrates additional methods for the synthesis ofamino-imidazole compounds defined as Formula I. Treatment ofN—O-dimethyl hydroxylamine hydrochloride with trimethylaluminum in1,2-dichloroethane followed by the addition of ester 18, prepared asdescribed above and heating at about 30° C. to about 80° C., where atemperature of about 50° C. is preferred, affords imidazole 23. Additionof an organometallic reagent 24 wherein Z is defined as lithium halide,magnessium halide, potassium halide, where lithium halide is preferred,to a solution of amide 23 in a solvent such as tetrahydrofuran,methylene chloride, or diethyl ether, from a temperature about −78° C.to about 30° C., where a range of about −20° C. to about 0° C. ispreferred affords 25. Addition of 25 to a mixture of hydroxyi aminehydrochloride and potassium acetate in a lower alcoholic solvent, wherein ethanol is preferred, at about 23° C., yields oxime 26 as a mixtureof isomers. Treatment of an acetone solution of oxime 26 at about 0° C.with aqueous hydroxide followed by paratoluenesulfonyl chloride yields amixture of O-sulfonyl compound following extractive workup. Dissolutionof the crude material in a non-polar solvent such as benzene, hexanes,or toluene, wherein benzene is preferred, and application to a column ofalumina followed by elution with chloroform-methanol (about 10:1) afterapproximately five minutes provides a compound of Formula I.

Scheme 6 illustrates methods suitable for preparing amino-imidazolecompounds of formula I. Compound of Formula I, 27 can be prepared usingmethods described above. Converstion of ester I, 27 to alcohol ofcompounds I, 28 can be accomplished by treatment of ester I, 27.Compounds of formula I, 28 may be oxidized using standard oxidationmethod known in art, such as, e.g., Dess-Martin reagents, Swernoxidation, or use of SO₃-pyridine, CrO₃, where Swern oxidation ispreferred to provide compounds containing an aldehyde. The aldehyde canbe converted onto compounds of formula I, 29 using well-establishedreductive amination method by reacting the aldehyde with an appropriateamine 5A, with or without acid catalyst/ammonium acetate/dry agents(such as anhydrous Na₂SO₄ or MgSO₄), and a reducing agent, such assodium triacetoxy borohydride, sodium cyanoborohydride, or sodiumborohydride, or the corresponding polymer bound-NaBH₄, polymerbound-NaBH₃CN, or polymer bound-NaB(OAc)₃H, or any reducing agent (e.g.,hydrogenation) that is known in the literature for reducing an iminebond to an amine, in an appropriate solvent, such as dichloroethane,chloroform, THF, MeOH, ethanol, isopropanol, t-butanol or toluene, at atemperature from about room temperature to about reflux, preferably fromabout room temperature to about 65° C. Alternatively, the alcohol of I,28 can be converted to the corresponding alkyl or aryl sulfonate bytreatment of the alcohol with alkyl or aryl sulfonyl chloride (where inmesyl chloride is preferred) in a solvent such as methylene chloride,tetrahydrofuran, toluene wherein methylene chloride in the presence ofan amide such as triethylamine, diisopropyamine, pyridine, 2,6-lutidine,where in triethylamine is preferred at a temperature from −50° C. to 23°C. wherein −0° C. to 30° C. is preferred. The aryl or alkyl sulfonate isthen reacted with an alkali metal azide (wherein sodium azide ispreferred), in a polar solvent such as dimethylformamide,dimethylsulfoxide, alcohol, wherein ethanol is preferred produces acompound containing an azide. This intermediate azide may be reduced byexposing the azide to a noble metal catalyst, in a solvent such as ethylacetate, tetrahydrofuran, dioxane, or a mixture thereof, to anatmosphere of hydrogen gas at a pressure of about 1 to 100 atmospheres,where a preferred pressure of hygrogen gas is about one to about tenatmospheres. Palladium is the preferred noble metal catalyst and thereaction affords the amine group. The amine group can then be convertedto compounds of Formula I, 29 using the reductive amination conditionsdescribed above.

Referring to Scheme 7, treatment of a solution of bromoimidazole 30 witha base, such as sodium hydride, potassium hydride, lithium hydride,cesium carbonate, sodium hydroxide, potassium hydroxide, cesiumhydroxide, lithium diisopropyl amide, sodium amide, potassiumhexamethyldisilazide, sodium hexamethyldisilazide, sodium tert-butoxide,or potassium teft-butoxide, in a reaction inert solvent such astetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide,or toluene, from about −20° C. to 150° C., where 20° C. to 100° C. ispreferred, in the absence or presence of a phase transfer catalyst, suchas tetra-n-butylammonium chloride, tetra-n-butylammonium bromide,tetra-n-butylammonium iodide, benzyltrimethyl ammonium chloride,benzyltrimethyl ammonium bromide, or benzyltrimethyl ammonium fluoride,followed by the addition of an alkyl, allylic, or benzylic chloride,bromide, iodide, alkyl sulfonate, aryl sulfonate, or triflate, affordsimidazoles 31.

Treatment of 1-substituted-4-bromoimidazole (31) with an intermediate ofthe formula 32 or PG-NH2 (where PG is defined as (C═O)alkyl or benzoyl)and a palladium catalyst such as palladium (II) acetate, allyl palladiumchloride dimer, tris(dibenzylideneacetone)dipalladium (0),tris(dibenzylideneacetone)dipalladium (0) chloroform adduct, orpalladium (II) chloride, where palladium (II) acetate,tris(dibenzylideneacetone)dipalladium (0), andtris(dibenzylideneacetone)dipalladium (0) chloroform adduct arepreferred, and a phosphine ligand, preferably9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS) is preferred,and a base, such as cesium carbonate, or potassium phosphate (K₃PO₄),where potassium phosphate is preferred, in a reaction inert solvent,such as toluene, 1,4-dioxane, or tetrahydrofuran, from about 0° C. to150° C., where 20° C. to 110° C. is preferred, affords the coupledproduct 1. Alternatively, treatment of 1-substituted-4-bromoimidazole(31) with an intermediate of the formula 32 or PG-NH2 (where PG isdefined as (C═O)alkyl or benzoyl) and a diamine, such as1,2-ethylenediamine, N,N′-dimethylethylenediamine, orcis-1,2-diaminocyclohexane, preferably N,N′-dimethylethylenediamine, andcuprous chloride, bromide or iodide, preferably cuprous iodide, in thepresence of a small amount of water, preferably about 1% to about 4%water, in a reaction inert solvent such as 1,2-dimethoxyethane, diglyme,t-butyl methyl ether, tetrahydrofuran, benzene or toluene, preferablytoluene, at a temperature of about 40° C. to about 150° C., preferablyabout 80° C. to about 120° C. to yield the compound of formula I orcompounds of formula 33. In the case of compound 33, this can beconverted to compounds of forumla 2A using standard methods describedabove.

The starting materials used in the procedures of the above Schemes, thesyntheses of which are not described above, are either commerciallyavailable, known in the art or readily obtainable from known compoundsusing methods that will be apparent to those skilled in the art.

The compounds of Formula I, and the intermediates shown in the abovereaction schemes, may be isolated and purified by conventionalprocedures, such as recrystallization or chromatographic separation,such as on silica gel, either with an ethyl acetate/hexane elutiongradient, a methylene chloride/methanol elution gradient, or achloroform/methanol elution gradient. Alternatively, a reverse phasepreparative HPLC or chiral HPLC separation technique may be used.

In each of the reactions discussed or illustrated above, pressure is notcritical unless otherwise indicated. Pressures from about 0.5atmospheres to about 5 atmospheres are generally acceptable, and ambientpressure, i.e., about 1 atmosphere, is preferred as a matter ofconvenience.

A compound of the Formula I of the present invention, orpharamaceutically acceptable salt thereof, may be administered tomammals via either the oral, parenteral (such as subcutaneous,intravenous, intramuscular, intrasternal and infusion techniques),rectal, intranasal, topical or transdermal (e.g., through the use of apatch) routes. In general, these compounds are most desirablyadministered in doses ranging from about 0.1 mg to about 1000 mg perday, in single or divided doses (i.e., from 1 to 4 doses per day),although variations will necessarily occur depending upon the species,weight, age and condition of the subject being treated, as well as theparticular route of administration chosen. However, a dosage level thatis in the range of about 0.1 mg/kg to about 5 gm/kg body weight per day,preferably from about 0.1 mg/kg to about 100 mg/kg body weight per day,is most desirably employed. Nevertheless, variations may occur dependingupon the species of animal being treated and its individual response tosaid medicament, as well as on the type of pharmaceutical formulationchosen and the time period and interval at which such administration iscarried out. In some instances, dosage levels below the lower limit ofthe aforesaid range may be more than adequate, while in other casesstill larger doses may be employed without causing any harmful sideeffects, provided that such higher dosage levels are first divided intoseveral small doses for administration throughout the day. Varationsbased on the aforementioned dosage range may be made by a physicain ofordinary skill.

A compound of the Formula I of the present invention may be administeredalone or in combination with pharmaceutically acceptable carriers ordiluents by either of the routes previously indicated, and suchadministration may be carried out in single or multiple doses. Suitablepharmaceutical carriers include solid diluents or fillers, sterileaqueous media and various non-toxic organic solvents, etc. Thepharmaceutical compositions formed by combining a compound of theFormula I, or a pharmaceutically acceptable salt thereof, with apharmaceutically acceptable inert carrier, can then be readilyadministered in a variety of dosage forms such as tablets, capsules,lozenges, troches, hard candies, powders, sprays, creams, salves,suppositories, jellies, gels, pastes, lotions, ointments, aqueoussuspensions, injectable solutions, elixirs, syrups, and the like.Moreover, oral pharmaceutical compositions may be suitably sweetenedand/or flavored.

For oral administration, tablets containing various excipients such asmicrocrystalline cellulose, sodium citrate, calcium carbonate, dicalciumphosphate and glycine may be employed along with various disintegrantssuch as starch (preferably corn, potato or tapioca starch),methylcellulose, alginic acid and certain complex silicates, togetherwith granulation binders such as polyvinylpyrrolidone, sucrose, gelatinand acacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc are often useful for tabletting purposes.Solid compositions of a similar type may also be employed as fillers ingelatin capsules. Preferred materials in this connection include lactoseor milk sugar as well as high molecular weight polyethylene glycols.When aqueous suspensions and/or elixirs are desired for oraladministration, the active ingredient may be combined with varioussweetening or flavoring agents, coloring matter or dyes, and, if sodesired, emulsifying and/or suspending agents as well, together withsuch diluents as water, ethanol, propylene glycol, glycerin and variouslike combinations thereof.

For parenteral administration, solutions containing a compound of theFormula I of the present invention or a pharmaceutically acceptable saltthereof in either sesame or peanut oil, in aqueous propylene glycol orin sterile aqueous solutions may be employed. The aqueous solutionsshould be suitably buffered (preferably pH greater than 8) if necessaryand the liquid diluent first rendered isotonic with sufficient saline orglucose. These aqueous solutions are suitable for intravenous injectionpurposes. The oily solutions are suitable for intraarticular,intramuscular and subcutaneous injection purposes. The preparation ofall these solutions under sterile conditions is readily accomplished bystandard pharmaceutical techniques well known to those skilled in theart.

The compounds of Formula I of the present invention are useful ininhibiting Aβ-peptide production (thus, gamma-secretase activity) inmammals, and therefore they are able to function as therapeutic agentsin the treatment of the aforementioned disorders and diseases in anafflicted mammal.

A specific compound of the Formula I can be determined to inhibitAβ-peptide production using biological assays known to those of ordinaryskill in the art, for example the assays described below.

The activity of compounds of the Formula I of the present invention ininhibiting gamma-secretase activity was determined in a solubilizedmembrane preparation generally according to the description provided inMcLendon et al. Cell-free assays for γ-secretase activity, The FASEBJournal (Vol. 14, December 2000, pp. 2383-2386). Using such assay,compounds of the present invention were determined to have an IC₅₀activity for inhibiting gamma-secretase activity of less than about 100micromolar. Preferred compounds of the invention are compounds that weredetermined to have an IC₅₀ activity for inhibiting gamma-secretaseactivity of less than about 1 micromolar.

The following Examples illustrate the present invention. It is to beunderstood, however, that the invention, as fully described herein andas recited in the claims, is not intended to be limited by the detailsof the following Examples.

EXAMPLES

General Procedure A:

Coupling Method for Amide Formation

a) EDC/HOBt/Trialkylamine Coupling Procedure

A mixture of a carboxylic acid (1.0 e.q.), amine (1.0 e.q.), HOBt(1.1-1.5 eq.), EDC (1.2-1.8 eq.) and a trialkylamine (triethylamine ordiisopropylethylamine) (3-6 eq.) in an appropriate solvent or a mixtureof solvents, for example methylene chloride, dichloroethane, THF, orDMF, was stirred at room temperature until product formation ordisappearance of starting material. The solvent was removed underreduced pressure, the residue taken up in ethyl acetate (or similarselected solvent such as methylene chloride or chloroform) and water.The organic layer was separated, washed with dilute HCl (if the desiredproduct contains a basic functional group, washing with dilute HCl maybe omitted), brine, and dried over sodium sulfate. The solvent was thenremoved at reduced pressure to provide product.

-   -   b) HATU/Trialkylamine Coupling Procedure

A mixture of a carboxylic acid (1.0 e.q.), amine (1.0 e.q.), HATU(1.1-1.5 eq.) and a trialkylamine (triethylamine ordiisopropylethylamine) (3-6 eq.) in an appropriate solvent or a mixtureof solvents, for example methylene chloride, dichloroethane, THF, orDMF, was stirred at room temperature until product formation ordisappearance of starting material. The solvent was removed underreduced pressure, the residue taken up in ethyl acetate (or similarselected solvent such as methylene chloride or chloroform) and water.The organic layer was separated, washed with dilute HCl (if the desiredproduct contains a basic functional group, washing with dilute HCl maybe omitted), brine, and dried over sodium sulfate. The solvent was thenremoved at reduced pressure to provide product.

-   -   c) PyBOP/Trialkylamine Coupling Procedure

A mixture of a carboxylic acid (1.0 e.q.), amine (1.0 e.q.), PyBOP(1.1-1.5 eq.) and a trialkylamine (triethylamine ordiisopropylethylamine) (3-6 eq.) in an appropriate solvent or a mixtureof solvents, for example methylene chloride, dichloroethane, THF, orDMF, was stirred at room temperature until product formation ordisappearance of starting material. The solvent was removed underreduced pressure, the residue taken up in ethyl acetate (or similarselected solvent such as methylene chloride or chloroform) and water.The organic layer was separated, washed with dilute HCl (if the desiredproduct contains a basic functional group, washing with dilute HCl maybe omitted), brine, and dried over sodium sulfate. The solvent wasremoved at reduced pressure to provide product.

-   -   d) HBTU/Trialkylamine Coupling Procedure

A mixture of a carboxylic acid (1.0 e.q.), amine (1.0 e.q.), HBTU(1.1-1.5 eq.), and a trialkylamine (triethylamine ordiisopropylethylamine) (3-6 eq.) in an appropriate solvent or a mixtureof solvents, for example methylene chloride, dichloroethane, THF, orDMF, was stirred at room temperature until product formation ordisappearance of starting material. The solvent was removed underreduced pressure, the residue taken up in ethyl acetate (or similarselected solvent such as methylene chloride or chloroform) and water.The organic layer was separated, washed with dilute HCl (if the desiredproduct contains a basic functional group, washing with dilute HCl maybe omitted), brine, and dried over sodium sulfate. The solvent wasremoved at reduced pressure to provide product.

-   -   e) Chloro-Alkylformate Coupling Procedure

A mixture of a carboxylic acid (1 eq.) and triethylamine (eq.) wasdissolved in an appropriate solvent, such as DMF and cooled to −23°C./so-butyl formate (1 eq.) was added dropwise with stirring. Afterstirring for a period of time (form 15 min to 2 hr), a 2-amino-thiazoleor an amine (1 eq.) was added and stirring continued for an additional30 min at −23° C. The mixture was then warmed to room temperature untilamide formation (typically overnight). The mixture was quenched withwater and brine and extracted with an appropriate solvent such as ethylacetate, methylene chloride or chlorform. The organic layer was washedwith dilute NaHSO₄, NaHCO₃ and brine and the solvent was removed underreduced pressure to provide product. Purification may be necessary.

f) Trimethylaluminum Coupling Procedure

A mixture of an amine or an amino-thiazole (1-2 eq.), 2Mtrimethylaluminum was made in an appropriate solvent, such as THF,toluene, xylene, methylene chloride, or dichloroethane, or a mixture ofsolvents such as THF/toluene. The mixture was stirred at roomtemperature for 15 min to 2 hr, then an ester (1 eq.) was added. Theresulting mixture was stirred at temperature between room temperature toreflux until product formation. The mixture was carefully quenched withRochelle salt and extracted with an appropriate solvent such as ethylacetate or methylene chloride, filtered through celite. The organiclayer was washed with dilute HCl, neutralized with saturated sodiumbicarbonate, and washed with brine. The organic layer was separated,dried and concentrated to give the desired amide. Purification may benecessary.

General Procedure B:

Method for Reductive Amination

a) Sodium Triacetoxyborohydride

An amine (1-4 eq.) in dichloroethane or THF was added to a solution of aketone (1 eq.), NaBH(Oac)₃ (1-3 eq.) and acetic acid (1-3 eq.) indichloroethane or THF. The mixture was stirred at room temperature untilproduct formation or disappearance of starting material. The mixture wasquenched with diluted base, extracted with methylene chloride or otherappropriate solvent such as chloroform or ethyl acetate. The organiclayer was separated, dried and concentrated to give the desired amide.Purification may be necessary.

b) Sodium Cyanoborohydride

A mixture of a ketone or aldehyde (1 eq.), an amine (1-20 eq.), sodiumcyanoborohydride (1-5 eq.), acetic acid (1-3 eq.), sodium acetate (1-3eq.), anhydrous sodium sulfate in dichloroethane or THF was stirred atroom temperature to 60° C., preferably heated at 35-50° C. until productformation. The mixture was quenched with diluted base, extracted withmethylene chloride or other appropriate solvent such as chloroform orethyl acetate. The organic layer was separated, dried and concentratedto give the desired amide. Purification may be necessary.

c) Potassium Formate and Palladium Acetate

A solution of an aldehyde or a ketone (1 eq.) and an amine (1 eq.) indry DMF was stirred at room temperature for 4 hr, in the presence ofmolecular sieves. To the resulting reaction mixture were added potassiumformate (2 eq.) and palladium acetate (catalytic amount, 0.02 eq.). Themixture was heated at 40-60° C. to complete reaction (TLC) and aftercooling it was diluted with ice-water. The mixture was extracted with anappropriate solvent (such as methylene chloride, ethyl acetate, orchloroform). The organic layer was separated, dried and concentrated togive the desired amide. Purification may be necessary.

General Procedure C:

Sodium Borohydride Reduction of Ketone or Aldehyde

A mixture of an aldehyde or a ketone (1 eq.) and sodium borohydride(1-10 eq.) in an appropriate solvent (methanol or ethanol) was stirredat 0° C. to room temperature for 10 minutes to complete reaction (TLC).The mixture was concentrated to a small volume, quenched with water,extracted with an appropriate solvent (such as methylene chloride, ethylacetate, or chloroform). The organic layer was separated, dried andconcentrated to give the desired amide. Purification may be necessary.

General Procedure D:

N-tBOC Deprotecting Procedure

To a solution of N-tBOC compound in 1,4-dioxane (0.03-0.09 M) was added4 N HCl in 1,4-dioxane or anhydrous HCl gas under nitrogen. The reactionmixture was stirred at room temperature for 1-24 hrs until all thestarting material consumed (TLC). The solution was concentrated andpumped in vacuo. The final HCl salt of the corresponding amine wastypically used without further purification.

General Procedure E:

Conjugate Addition to Nitroimidazole

To a suspension of 4-nitroimidazole (2.0 equiv.) in acetonitrile isadded DBU (1.0 equiv) followed by enone (1.0 equiv.). The reaction isheated for 12-24 hrs and the solvent removed in vacuo. The resultantsolids are removed by filtration with methylene chloride and theresultant oil concentrated and purified by silica gel chromatography toprovide the desired nitroimidazole.

General Proceudre F:

Alkylation of Nitroimidazole

To a suspension of 4-nitroimidazole (1.0 equiv.) in dimethylformamide atrt under a nitrogen atmosphere is added sodium hydride (1.2 equiv.)portionwise. The reaction is stirred for 15-30 min. And then theappropriate alkylhalide or alkyl mesylate is added. The mixture isstirred for 12-24h at 50° C., cooled to 0° C., and quenched with water.The aqueous layer is extrated with methylene chloride, dried, andpurified by silica gel chromatography to provide the desirednitroimidazole.

General Procedure G:

Reduction of Nitroimidazole

To a solution of the nitroimidazole (1.0 equiv.) in ethylacetate isadded palladium on carbon (0.25 w/w %). The reaction is hydrogenated @40-60 psi for 2-6 hrs and filtered over a pad of celite using ethylacetate. The majority of the ethylacetate is removed in vacuo and thesolution of the amine in the remaining ethylacetate is used withoutfurther purification.

General Procedure H:

Reduction of Nitroimidazole-ester followed by Reductive Amination

To a solution of 3-Methyl-3-(4-nitro-imidazol-1-yl)-butyric acid methylester (1.0 equiv.) in methylene chloride at −78° C. is added DIBAL (2equiv.) dropwise. The reaction is stirred for 1 h, quenched withethylacetate, removed from cooling bath, and stirred for 10 min. To thereaction is added water and allowed to warm to rt and stir for 1 h. Thereaction is diluted with methylene chloride, Na₂SO₄ is added and thereaction filtered through celite. The solvent is removed to afford2-Methyl-2-(4-nitro-imidazol-1-yl)-propionaldehyde which is used in thenext step without further purification.

To a solution of 2-Methyl-2-(4-nitro-imidazol-1-yl)-propionaldehyde (1equiv.) in methylene chloride is added an appropriate amine (2 equiv.)and 4A molecular sieves. The reaction is stirred for 4-6 hours and anappropriate hydride reducing agent such as sodium triacetoxyborohydride(2 equiv.) is added. The reaction is stirred for 6-24h, quenched withsodium bicarbonate, and the aqueous layer extracted with methylenechloride. The solvent is removed and residue purified by silica gelchromatography to provide the desired nitroimidazole.

The following compounds were prepared by methods analogous to thosedescribed above for General Procedure E:

3-(4-Nitro-imidazol-1-yl)-butyric acid methyl ester

4-nitroimidazole was reacted with methyl-3-methylacrylate to provide thetitle compound: 1H NMR (400 MHz, CDCl3) 1.62 (d, 3H, J=7.0 Hz), 2.81 (d,2H, J=7.0 Hz), 3.66 (s, 3H), 4.78 (m, 1H), 7.53 (d, 1H, J=1.6 Hz), 7.82(d, 1H, J=1.6 Hz); MS m/z 214.1(M+1).

3-Methyl-3-(4-nitro-imidazol-1-yl)-butyric acid methyl ester

4-nitroimidazole was reacted with methyl-3,3-dimethylacrylate to providethe title compound: ¹H NMR (400 MHz, CDCl3) 1.74 (s, 6H), 2.81 (s, 2H),3.57 (s, 3H), 7.57 (d, 1H, J=1.3 Hz), 7.90 (d, 1H, J=1.6 Hz); MS m/z228.2 (M+1).

The following compounds were prepared by methods analogous to thatdescribed above for General Procedure F:

2-Methyl-2-(4-nitro-imidazol-1-yl)-propionic acid methyl ester

4-nitroimidazole was alkylated with 2-Bromo-2-methyl-propionic acidmethyl ester to provide the title compound: ¹H NMR (400 MHz, CDCl3) 1.89(s, 6H), 3.78 (s, 3H), 7.59 (d, 1H, J=1.7 Hz), 7.89 (s, 1H, J=1.7 Hz);MS 214.1 m/z (M+1).

1-(1-Ethyl-propyl)-4-nitro-1H-imidazole

4-nitroimidazole was alkylated with 3-bromopentane to provide the titlecompound: 1H NMR (400 MHz, CDCl3) 0.84-0.90 (m, 6H), 1.71-1.82 (m, 2H),1.86-1.96 (m, 2H), 3.79 (p, 1H, J=4.8 Hz), 7.41 (d, 1H, J=1.6 Hz), 7.73(d, 1H, J=1.3 Hz); MS 184.2 m/z (M+1).

4-(4-N itro-imidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester

4-nitroimidazole was alkylated with4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester toprovide the title compound: C13 NMR (100 MHz, CDCl3) 28.5, 33.2, 42.7,56.8, 80.7, 117.5, 134.4, 154.5; MS 297.1 m/z (M+1).

(4-Nitro-imidazol-1-yl)-acetic acid methyl ester

4-nitroimidazole was alkylated with bromo-acetic acid methyl ester toprovide the title compound: ¹H NMR (400 MHz) 3.82 (s, 1H), 4.80, (s,2H), 7.47 (d, 1H, J=1.7 Hz), 7.84 (d, 1H, J=1.7 Hz); gc/ms m/z 185 (M).

2-Methyl-2-(2-methyl-4-nitro-imidazol-1-yl)-propionic acid methyl ester

2-methyl-4-nitro-imidazole was alkylated with bromo-acetic acid methylester to provide the title compound: MS m/z 228.2 (M+1).

1-(2-Methoxy-1,1-dimethyl-ethyl)-4-nitro-1H-imidazole

2-Methyl-2-(4-nitro-imidazol-1-yl)-propionic acid methyl ester wasreduced using sodium borohydride in methanol and the resultant alcoholwas alkylated with methyl iodide using sodium hydride as base to providethe title compound: H1 NMR (400 MHz, CDCl3) 1.53 (s, 6H), 3.25 (s, 3H),3.38 (s, 2H), 7.53 (s, 1H), 7.88 (s, 1H).

4-(4-Nitro-imidazol-1-yl)-benzoic acid methyl ester

4-nitroimidazole (1 equiv) was combined with 4-iodo-methylbenzoate (1.2equiv), cesium carbonate (1.0 equiv), copper (I) triflate (0.05 equiv),in DMF and heated overnight at 100° C. The solid was filtered and washedwith methylene chloride, the resultant solvent was concentrated, andresidue purified by silica gel chromatography to provide the titlecompound: MS m/z 248.2 (M+1).

(2,2-Dimethyl-propyl)-methyl-[2-methyl-2-(4-nitro-imidazol-1-yl)-Propyl]-amine

(2,2-Dimethyl-propyl)-[2-methyl-2-(4-nitro-imidazol-1-yl)-propyl]-aminewas treated with formalin and formic acid at 85° C. for 5h, quenchedwith aqueous sodium bicarbonate, extracted with methylene chloride,dried, concentrated, and the resultant residue purified bychromatography to afford the title compound: H1 NMR (400 MHz, CDCl3)0.74 (s,9H), 1.52 (s, 6H), 2.2 (s, 2H), 2.8 (s, 2H), 7.6 (s, 1H), 7.9(s, 1H); MS m/z 255.3 (M+1).

The following compounds were prepared by methods analogous to thatdescribed above for General Procedure H:

4-[2-Methyl-2-(4-nitro-imidazol-1-yl)-propyl]-morpholine

2-Methyl-2-(4-nitro-imidazol-1-yl)-propionaldehyde was reacted withmorpholine to provide the title compound: MS m/z 255.1 (M+1).

1-(1,1-Dimethyl-2-pyrrolidin-1-yl-ethyl)-4-nitro-1H-imidazole

2-Methyl-2-(4-nitro-imidazol-1-yl)-propionaldehyde was reacted withpyrrolidine to provide the title compound: H1 NMR (400 MHz, CDCl3) 1.56(s, 6H), 1.61 (m, 4H), 2.35 (m, 4H), 2.70 (m, 4H), 7.60 (s,1H), 7.92 (s,1H); MS m/z 239.2 (M+i).

(2,2-Dimethyl-propyl)-[2-methyl-2-(4-nitro-imidazol-1-yl)-propyl]-amine

2-Methyl-2-(4-nitro-imidazol-1-yl)-propionaldehyde was reacted with2,2-dimethyl-Dronyl amine to provide the title compound: H1 NMR (400MHz, CDCl3) 0.74 (s,9H), 1.52 (s, 6H), 2.2 (s, 2H), 2.8 (s, 2H), 7.6 (s,1H), 7.9 (s, 1H); MS m/z 255.3 (M+1).

[2-Methyl-2-(4-nitro-imidazol-1-yl)-propyl]-(2,2,2-trifluoro-ethyl)-amine

2-Methyl-2-(4-nitro-imidazol-1-yl)-propionaldehyde was reacted with2,2,2-trifluoro-ethyl amine to provide the title compound: H1 NMR (400MHz, CDCl3) 1.59 (s, 6H), 2.98 (s, 2H), 3.10 (m, 2H), 7.56 (s, 1H), 7.90(s, 1H) MS m/z267.3 (M+1).

1-[2-Methyl-2-(4-nitro-imidazol-1-yl)-propyl]-piperidine

2-Methyl-2-(4-nitro-imidazol-1-yl)-propionaldehyde was reacted withpiperdine to provide the title compound: C13 NMR (100 MHz, CDCl3) 23.8,25.6, 26.6, 57.0, 60.9, 69.2, 118.3, 134.4; MS m/z 253.3 (M+1).

2,6-Dimethyl-4-[2-methyl-2-(4-nitro-imidazol-1-yl)-propyl]-morpholine

2-Methyl-2-(4-nitro-imidazol-1-yl)-propionaldehyde was reacted withcis-2,6-dimethyl morpholine to provide the title compound: C13 NMR (100MHz, CDCl3) 19.0, 25.7, 60.8, 61.5, 68.5, 72.0, 118.0, 134.5; MS m/z283.2 (M+1).

Dimethyl-[2-methyl-2-(4-nitro-imidazol-1-yl)-propyl]-amine

2-Methyl-2-(4-nitro-imidazol-1-yl)-propionaldehyde was reacted withdimethyl amine to provide the title compound: H1 NMR (400 MHz, CDCl3)1.50 (s, 6H), 2.00 (s, 6H), 2.40 (s, 2H), 7.55 (s, 1H), 7.89 (s, 1H).

1-Methyl-4-[2-methyl-2-(4-nitro-imidazol-1-yl)-propyl]-piperazine

2-Methyl-2-(4-nitro-imidazol-1-yl)-propionaldehyde was reacted withN-methyl piperazine to provide the title compound: MS m/z 268.2 (M+1).

The following compounds were prepared by methods analogous to thatdescribed above for General Procedure G:

2-(4-Amino-imidazol-1-yl)-2-methyl-propionic acid methyl ester

2-Methyl-2-(4-nitro-imidazol-1-yl)-propionic acid methyl ester washydrogenated to provide the title compound: MS m/z 184.1 (M+1).

1-(1-Ethyl-propyl)-1H-imidazol-4-ylamine

1-(1-Ethyl-propyl)-4-nitro-1H-imidazole was hydrogenated to provide thetitle compound: MS m/z 154.1 (M+1).

3-(4-Amino-imidazol-1-yl)-butyric acid methyl ester

3-(4-Nitro-imidazol-1-yl)-butyric acid methyl ester was hydrogenated toprovide the title compound: MS m/z 184.2 (M+1).

3-(4-Amino-imidazol-1-yl)-3-methyl-butyric acid methyl ester

3-Methyl-3-(4-nitro-imidazol-1-yl)-butyric acid methyl ester washydrogenated to provide the title compound: MS m/z 198.1 (M+1).

4-(4-Amino-imidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester

4-(4-Nitro-imidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl esterwas hydrogenated to provide the title compound.

1-(1,1-Dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-ylamine

4-[2-Methyl-2-(4-nitro-imidazol-1-yl)-propyl]-morpholine washydrogenated to provide the title compound; MS m/z 225.3 (M+1).

1-(1,1-Dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-ylamine1-(1,1-Dimethyl-2-pyrrolidin-1-yl-ethyl)-4-nitro-1H-imidazole washydrogenated to provide the title compound; MS m/z 209.1 (M+1).

1-[2-(2,2-Dimethyl-propylamino)-1,1-dimethyl-ethyl]-1H-imidazol-4-ylamine

(2,2-Dimethyl-propyl)-[2-methyl-2-(4-nitro-imidazol-1-yl)-propyl]-aminewas hydrogenated to provide the title compound; MS m/z 253.3 (M+1).

1-[1,1-Dimethyl-2-(2,2,2-trifluoro-ethylamino)-ethyl]-1H-imidazol-4-ylamine

[2-Methyl-2-(4-nitro-imidazol-1-yl)-propyl]-(2,2,2-trifluoro-ethyl)-aminewas hydrogenated to provide the title compound; MS m/z 237.2 (M+1).

1-(1,1-Dimethyl-2-piperidin-1-yl-ethyl)-1H-imidazol-4-ylamine

1-[2-Methyl-2-(4-nitro-imidazol-1-yl)-propyl]-piperidine amine washydrogenated to provide the title compound; MS m/z 223.2 (M+1).

1-[2-(2,6-Dimethyl-morpholin-4-yl)-1,1-dimethyl-ethyl]-1H-imidazol-4-ylamine

2,6-Dimethyl-4-[2-methyl-2-(4-nitro-imidazol-1-yl)-propyl]-morpholinewas hydrogenated to provide the title compound; MS m/z 253.2 (M+1).

1-(2-Dimethylamino-1,1-dimethyl-ethyl)-1H-imidazol-4-ylamine

Dimethyl-[2-methyl-2-(4-nitro-imidazol-1-yl)-propyl]-amine washydrogenated to provide the title compound; MS m/z 183.3 (M+1).

(4-Amino-imidazol-1-yl)-acetic acid methyl ester

(4-Nitro-imidazol-1-yl)-acetic acid methyl ester was hydrogenated toprovide the title compound: Gc/MS m/z=185 (R_(T)=3.49 min.).

2-(4-Amino-2-methyl-imidazol-1-yl)-2-methyl-propionic acid methyl ester

2-Methyl-2-(2-methyl-4-nitro-imidazol-1-yl)-propionic acid methyl esterwas hydrogenated to provide the title compound.

1-(2-Methoxy-1,1-dimethyl-ethyl)-1H-imidazol-4-ylamine

1-(2-Methoxy-1,1-dimethyl-ethyl)-4-nitro-1H-imidazole was hydrogenatedto provide the title compound: MS m/z 170.2 (M+1).

4-(4-Amino-imidazol-1-yl)-benzoic acid methyl ester

4-(4-Nitro-imidazol-1-yl)-benzoic acid methyl ester was hydrogenated toprovide the title compound: MS m/z 218.2 (M+1).

1-{2-[(2,2-Dimethyl-propyl)-methyl-amino]-1,1-dimethyl-ethyl}-1H-imidazol-4-ylamine

(2,2-Dimethyl-propyl)-methyl-[2-methyl-2-(4-nitro-imidazol-1-yl)-propyl]-aminewas hydrogenated to provide the title compound: MS m/z 239.2 (M+1).

1-[1,1-Dimethyl-2-(4-methyl-piperazin-1-yl)-ethyl]-1H-imidazol-4-ylamine

1-Methyl-4-[2-methyl-2-(4-nitro-imidazol-1-yl)-propyl]-piperazine washydrogenated to provide the title compound.

The following compounds were prepared by methods analogous to thosedescribed above for General Procedure A, general coupling procedure (e):

2-[4-(2-tert-Butoxycarbonylamino-pentanoylamino)-imidazol-1-yl]-2-methyl-Propionicacid methyl ester

2-(4-Amino-imidazol-1-yl)-2-methyl-propionic acid methyl ester wascoupled with (L)—N-Boc norvaline to provide the title compound: MS m/z353.3 (M+1).

{1-[1-(1-Ethyl-propyl)-1 Himidazol-4-ylcarbamoyl]-butyl}-carbamic acidtert-butyl ester

1-(1-Ethyl-propyl)-1H-imidazol-4-ylamine was coupled with (L)-N-Bocnorvaline to provide the title compound: MS m/z 383.1 (M+1).

3-[4-(2-tert-Butoxycarbonylamino-pentanoylamino)-imidazol-1-yl]-butyricacid methyl ester

3-(4-Amino-imidazol-1-yl)-butyric acid methyl ester was coupled with(L)-N-Boc norvaline to provide the title compound: MS m/z 383.3 (M+1).

3-[4-(2-tert-Butoxycarbonylamino-pentanoylamino)-imidazol-1-yl]-3-methyl-butyricacid methyl ester

3-(4-Amino-imidazol-1-yl)-3-methyl-butyric acid methyl ester was coupledwith (L)-N-Boc norvaline to provide the title compound: C13 NMR (100MHz, CDCl3) 13.9, 19.0, 28.1, 28.5, 36.1, 47.2, 51.9, 54.4, 56.3, 79.7,104.8, 131.3, 138.0, 155.6, 169.8, 170.0; MS m/z 397.3 (M+1).

3-[4-(2-tert-Butoxycarbonylamino-propionylamino)-imidazol-1-yl]-3-methyl-butyricacid methyl ester

4-(4-Amino-imidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl esterwas coupled with (L)-N-Boc alanine to provide the title compound: C13NMR (100 MHz, CDCl3) 19.9, 28.1, 28.2, 28.5, 47.1, 50.1, 51.9, 56.3,79.7, 104.8, 131.1, 138.1, 155.4, 170.0, 170.2; MS m/z369.1 (M+1).

2-[4-(2-tert-Butoxycarbonylamino-4-methyl-pentanoylamino)-imidazol-1-yl]-2-methyl-propionicacid methyl ester

2-(4-Amino-imidazol-1-yl)-2-methyl-propionic acid methyl ester wascoupled with (L)-N-Boc isoleucine to provide the title compound:

2-[4-(2-tert-Butoxycarbonylamino-propionylamino)-imidazol-1-yl]-2-methyl-propionicacid methyl ester

2-(4-Amino-imidazol-1-yl)-2-methyl-propionic acid methyl ester wascoupled with (L)-N-Boc alanine to provide the title compound.

{1-[1-(2-Methoxy-1,1-dimethyl-ethyl)-1H-imidazol-4-ylcarbamoyl]-butyl}-carbamicacid tert-butyl ester

1-(2-Methoxy-1,1-dimethyl-ethyl)-1H-imidazol-4-ylamine was coupled with(L)-N-Boc alanine to provide the title compound: MS m/z 369.3 (M+1).

General Procedure I

Ester Reduction

{1-[1-(2-Hydroxy-1,1-dimethyl-ethyl)-1H-imidazol-4-ylcarbamoyl]-butyl}-carbamicacid tert-butyl ester

To a solution of2-[4-(2-tert-Butoxycarbonylamino-pentanoylamino)-imidazol-1-yl]-2-methyl-propionicacid methyl ester (9.6 g, 25.2 mmol) in 100 mL of diethyl ether at 0° C.is added 1.0 M lithium aluminum hydride (37.9 mL, 37.9 mmol) indiethylether dropwise over 1 h. The reaction is stirred at 0° C. for 15min and warmed to rt for 1 h. The reaction is slowly quenched with 200mL of water and ethyl acetate (200 mL). The reaction is filtered and theaqueous is extracted with ethylacetate, dried, and concentrated. Theresultant residue is purified by silica gel chromatography to providethe title compound (5.8 g); MS m/z 355.3 (M+1).

The following compounds were prepared by methods analogous to thosedescribed above for General Procedure l:

{1-[1-(3-Hydroxy-1,1-dimethyl-propyl)-1H-imidazol-4-ylcarbamoyl]-butyl}-carbamicacid tert-butyl ester

3-[4-(2-tert-Butoxycarbonylamino-pentanoylamino)-imidazol-1-yl]-3-methyl-butyricacid methyl ester was reduced to provide the title compound: C13 NMR(100 MHz, CDCl3) 14.0, 18.9, 28.6, 28.9, 29.2, 36.5, 44.9, 54.1, 57.4,58.3, 79.9, 105.0, 131.4, 138.0, 155.7, 169.6; MS m/z 369.2 (M+1).

2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide

2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(2-hydroxy-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide was reduced toprovide the title compound: MS m/z 353.3 (M+1).

{1-[1-(2-Hydroxy-1,1-dimethyl-ethyl)-1H-imidazol-4-ylcarbamoyl]-3-methyl-butyl}-carbamicacid tert-butyl ester

2-[4-(2-tert-Butoxycarbonylamino-4-methyl-pentanoylamino)-imidazol-1-yl]-2-methyl-propionicacid methyl ester was reduced to provide the title compound.

{1-[1-(2-Hydroxy-1,1-dimethyl-ethyl)-1H-imidazol-4-ylcarbamoyl]-ethyl}-carbamicacid tert-butyl ester

2-[4-(2-tert-Butoxycarbonylamino-propionylamino)-imidazol-1-yl]-2-methyl-propionicacid methyl ester was reduced to provide the title compound.

General Procedure J

Swern Oxidation

{1-[1-(1,1-Dimethyl-2-oxo-ethyl)-1H-imidazol-4-ylcarbamoyl]-butyl}-carbamicacid tert-butyl ester

To a solution of oxalyl chloride (1.2 mL, 14.1 mmol) in 110 mL ofmethylene chloride at −78° C. is added DMSO (2.2 mL, 30.6 mmol)dropwiese. The reaction is stirred for 20 min. and{1-[1-(2-Hydroxy-1,1-dimethyl-ethyl)-1H-imidazol-4-ylcarbamoyl]-butyl}-carbamicacid tert-butyl ester (4.2g, 11.8 mmol) is added in 10 mL of methylenechloride. The reaction is stirred for 1 h, triethylamine (8.2 mL, 58.9mmol) is added, and the reaction warmed to 0° C. for 20 min. Thereaction is quenched with 100 mL of sodium bicarbonate, extracted withmethylene chloride, dried, and concentrated to afford the title compound(4.5 g): MS m/z 353.2 (M+1).

The following compounds were prepared by methods analogous to thosedescribed above for General Procedure J:

{1-[1-(1,1-Dimethyl-3-oxo-propyl)-1H-imidazol-4-ylcarbamoyl]-butyl}-carbamicacid tert-butyl ester

Oxidation of{1-[1-(3-Hydroxy-1,1-dimethyl-propyl)-1H-imidazol-4-ylcarbamoyl]-butyl}-carbamicacid tert-butyl ester afforded the title compound: C13 NMR (100 MHz,CDCl3) 13.9, 19.0, 28.5, 28.6, 35.9, 54.5, 55.0, 56.1, 79.8, 104.6,126.1, 131.1, 131.2, 135.4, 155.6, 170.0, 199.0; MS m/z 367.2 (M+1).

{1-[1-(1,1-Dimethyl-2-oxo-ethyl)-1H-imidazol-4-ylcarbamoyl]-3-methyl-butyl}-carbamicacid tert-butyl ester

Oxidation of{1-[1-(2-Hydroxy-1,1-dimethyl-ethyl)-1H-imidazol-4-ylcarbamoyl]-3-methyl-butyl}-carbamicacid tert-butyl ester afforded the title compound.

{1-[1-(1,1-Dimethyl-2-oxo-ethyl)-1H-imidazol-4-ylcarbamoyl]-ethyl}-carbamicacid tert-butyl ester

Oxidation of{1-[1-(2-Hydroxy-1,1-dimethyl-ethyl)-1H-imidazol-4-ylcarbamoyl]-ethyl}-carbamicacid tert-butyl ester afforded the title compound.

2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-3-oxo-prolyl)-1H-imidazol-4-yl]-amide

Oxidation of 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(3-hydroxy-1,1-dimethyl-propyl)-1H-imidazol-4-yl]-amide afforded thetitle compound.

2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide afforded the titlecompound: MS m/z 419.4 (M+1)

Oxidation of2-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoylamino]-imidazol-1-yl}-2-methyl-propionicacid methyl ester.

The following compounds were prepared by methods analogous to thosedescribed above for General Procedure B:

{1-[1-(1,1-Dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-vicarbamoyl]-butyl}-carbamicacid tert-butyl ester

Reductive amination of{1-[1-(1,1-Dimethyl-2-oxo-ethyl)-1H-imidazol-4-ylcarbamoyl]-butyl}-carbamicacid tert-butyl ester with pyrrolidine afforded the title compound: MSm/z 408.3 (M+1).

{1-[1-(1,1-Dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-ylcarbamoyl]-butyl}-carbamicacid tert-butyl ester

Reductive amination of{1-[1-(1,1-Dimethyl-2-oxo-ethyl)-1H-imidazol-4-ylcarbamoyl]-butyl}-carbamicacid tert-butyl ester with morpholine afforded the title compound: MSm/z 424.3 (M+1).

{1-[1-(1,1-Dimethyl-3-pyrrolidin-1-yl-propyl)-1H-imidazol-4-ylcarbamoyl]-butyl}-carbamicacid tert-butyl ester

Reductive amination of{1-[1-(1,1-Dimethyl-3-oxo-propyl)-1H-imidazol-4-ylcarbamoyl]-butyl}-carbamicacid tert-butyl ester with pyrrolidine afforded the title compound: C13NMR (100 MHz, CDCl3) 13.9, 19.0, 28.5, 28.6, 35.9, 54.5, 55.0, 56.1,79.8, 104.6, 126.1, 131.1, 131.2, 135.4, 155.6, 170.0, 199.0; MS m/z367.2 (M+1).

{1-[1-(1,1-Dimethyl-3-morpholin-4-yl-propyl)-1H-imidazol-4-ylcarbamoyl]-butyl}-carbamicacid tert-butyl ester

Reductive amination of{1-[1-(1,1-Dimethyl-3-oxo-propyl)-1H-imidazol-4-ylcarbamoyl]-butyl}-carbamicacid tert-butyl ester with morpholine afforded the title compound: C13NMR (100 MHz, CDCl₃) 14.0, 19.0, 28.3, 28.5, 28.7, 36.3, 39.7, 53.9,54.3, 57.3, 67.1, 79.5, 105.0, 131.3, 138,0,155.6, 169.8; MS m/z 438.2(M+1).

{1-[1-(1,1-Dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-ylcarbamoyl]-ethyl}-carbamicacid tert-butyl ester

Reductive amination of{1-[1-(1,1-Dimethyl-2-oxo-ethyl)-1H-imidazol-4-ylcarbamoyl]-ethyl}-carbamicacid tert-butyl ester with pyrrolidine afforded the title compound.

{1-[1-(1,1-Dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-ylcarbamoyl]-3-methyl-butyl}-carbamicacid tert-butyl ester

Reductive amination of{1-[1-(1,1-Dimethyl-2-oxo-ethyl)-1H-imidazol-4-ylcarbamoyl]-3-methyl-butyl}-carbamicacid tert-butyl ester with pyrrolidine afforded the title compound.

{1-[7-(2,2-Dimethyl-propyl)-5,5-dimethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-1-ylcarbamoyl]-butyl}-carbamicacid tert-butyl ester

Reductive amination of{1-[1-(1,1-Dimethyl-2-oxo-ethyl)-1H-imidazol-4-ylcarbamoyl]-butyl}-carbamicacid tert-butyl ester with 2,2-dimethyl propyl amine afforded(1-{1-[2-(2,2-Dimethyl-propylamino)-1,1-dimethyl-ethyl]-1H-imidazol-4-ylcarbamoyl}-butyl)-carbamicacid tert-butyl ester: MS m/z 424.5 (M+1). Treatment of the above aminewith formalin and formic acid at 85° C. followed by purificationafforded the title compound:

The following compounds were prepared by methods analogous to thosedescribed above for General Procedure D:

2-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-2-methyl-propionic acidmethyl ester

2-[4-(2-tert-Butoxycarbonylamino-pentanoylamino)-imidazol-1-yl]-2-methyl-propionicacid methyl ester was deprotected to afford the title compound: MS m/z283.1 (M+1).

2-Amino-pentanoic acid [1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide

{1-[1-(1-Ethyl-propyl)-1H-imidazol-4-ylcarbamoyl]-butyl}-carbamic acidtert-butyl ester was deprotected to afford the title compound: MS m/z253.1 (M+1).

3-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-butyric acid methyl ester

3-[4-(2-tert-Butoxycarbonylamino-pentanoylamino)-imidazol-1-yl]-butyricacid methyl ester was deprotected to afford the title compound: MS m/z283.2 (M+1).

3-[4-(2-Amino-pentanoylamino)-imidazol-1-vyl-3-methyl-butyric acidmethyl ester

3-[4-(2-tert-Butoxycarbonylamino-pentanoylamino)-imidazol-1-yl]-3-methyl-butyricacid methyl ester was deprotected to afford the title compound: MS m/z297.2 (M+1).

3-[4-(2-Amino-propionylamino)-imidazol-1-yl]-3-methyl-butyric acidmethyl ester

3-[4-(2-tert-Butoxycarbonylamino-propionylamino)-imidazol-1-yl]-3-methyl-butyricacid methyl ester was deprotected to afford the title compound: MS m/z269.2 (M+1).

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

{1-[1-(1,1-Dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-ylcarbamoyl]-butyl}-carbamicacid tert-butyl ester was deprotected to afford the title compound: MSm/z 308.3 (M+1).

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide{1-[1-(1,1-Dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-ylcarbamoyl]-butyl}-carbamicacid tert-butyl ester was deprotected to afford the title compound: MSm/z 324.3 (M+1). 2-Amino-pentanoic acid[1-(1,1-dimethyl-3-pyrrolidin-1-yl-propyl)-1H-imidazol-4-yl]-amide

{1-[1-(1,1-Dimethyl-3-pyrrolidin-1-yl-propyl)-1H-imidazol-4-ylcarbamoyl]-butyl}-carbamicacid tert-butyl ester was deprotected to afford the title compound: MSm/z 322.2 (M+1).

2-Amino-pentanoic acid[1-(1,1-dimethyl-3-morpholin-4-yl-propyl)-1H-imidazol-4-yl]-amide

{1-[1-(1,1-Dimethyl-3-morpholin-4-yl-propyl)-1H-imidazol-4-ylcarbamoyl]-butyl}-carbamicacid tert-butyl ester was deprotected to afford the title compound: C13NMR (100 MHz, CDCl3) 13.9, 19.0, 28.4, 28.5, 31.4, 36.8, 39.6, 53.9,54.9, 57.4, 66.9, 104.9, 130.8, 137.6, 172.1; MS m/z 338.2 (M+1).

2-Amino-4-methyl-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

{1-[1-(1,1-Dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-ylcarbamoyl]-3-methyl-butyl}-carbamicacid tert-butyl ester was deprotected to afford the title compound.

2-Amino-N-1,1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-Propionamide

{1-[1-(1,1-Dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-ylcarbamoyl]-ethyl}-carbamicacid tert-butyl ester was deprotected to afford the title compound.

2-Amino-pentanoic acid[1-(2-methoxy-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide

{1-[1-(2-Methoxy-1,1-dimethyl-ethyl)-1H-imidazol-4-ylcarbamoyl]-butyl}-carbamicacid tert-butyl ester was deprotected to afford the title compound: MSm/z 269.3 (M+1).

2-Amino-pentanoic acid[7-(2,2-dimethyl-propyl)-5,5-dimethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-1-yl]-amide

{1-[7-(2,2-Dimethyl-propyl)-5,5-dimethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-1-ylcarbamoyl]-butyl}-carbamicacid tert-butyl ester was deprotected to provide the title compound: MSm/z 336.4 (M+1).

The following Examples were prepared by methods analogous to thosedescribed above for General Procedure A, coupling procedure (a):

Example 13-(4-[2-[2-(3,5-Difluoro-Phenyl)-acetylamino]-pentanoylamino]-imidazol-1-yl)-butyricacid methyl ester

3-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-butyric acid methyl esterwas coupled with (3,5-Difluoro-phenyl)-acetic acid to provide the titlecompound: Mixture of Diastereomers, MS m/z 437.2 (M+1). Thediastereomers were separated using using ChiralOD column, elute 85:15heptane:ethanol; Flow Rate 85 mL/min. Diastereomer #1 (R_(T)=9.39 min.)C13 NMR (100 MHz, CDCl3) 13.9, 18.9, 19.2, 21.5, 21.6, 28.3, 30.5, 35.9,41.9, 42.2, 43.0, 50.6, 50.7, 52.1, 53.1, 102.7, 104.9, 112.3, 112.5,132.2, 138.0, 169.2, 169.6, 170.7; MS m/z 437.2 (M+1) Diastereomer #2(R_(T)=13.6 min.) C13 NMR (100 MHz, CDCl3) 13.9, 18.9, 21.6, 35.8, 42.0,43.1, 50.8, 52.1, 53.1, 102.9, 104.8, 112.3, 112.6, 132.4, 137.9, 169.3,170.6; MS m/z 437.2 (M+1).

Example 23-{4-[2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoylamino]-imidazol-1-yl}-3-methyl-butyricacid methyl ester

3-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-3-methyl-butyric acidmethyl ester was coupled with (S)-2-hydroxy-3-methyl-butyric acid toprovide the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 16.0, 19.1,19.4, 28.1, 32.2, 35.5, 47.1, 51.9, 52.7, 56.4, 105.1, 131.1, 137.6,169.6, 170.0, 174.0.

Example 33-(4-[2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino]-imidazol-1-yl)-3-methyl-butyricacid methyl ester

3-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-3-methyl-butyric acidmethyl ester was coupled with (3,5-Difluoro-phenyl)-acetic acid toprovide the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 19.0, 27.9,28.1, 35.9, 42.7, 46.8, 51.8, 53.1, 56.3, 102.2, 102.5, 102.7, 105.1,112.2, 112.3, 112.4, 112.5, 131.3, 137.9, 139.2, 161.8, 164.2, 164.3,169.4, 169.9, 170.0; MS 451.2 m/z (M+1).

Example 43-{4-[2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoylamino]-imidazol-1-yl}-3-methyl-butyricacid methyl ester

3-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-3-methyl-butyric acidmethyl ester was coupled with (S)-2-hydroxy-3,3-dimethyl-butyric acid toprovide the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 19.1, 26.3,28.1, 35.2, 35.3, 47.1, 51.9, 52.7, 56.4, 79.9, 105.0, 131.0, 137.6,169.3, 170.1, 173.1; MS m/z 411.1 (M+1).

Example 5 2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid[1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid [1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide wascoupled with (S)-2-hydroxy-3,3-dimethyl-butyric acid to provide thetitle compound: C13 NMR (100 MHz, CDCl3) 10.8, 13.9, 19.0, 26.3, 28.8,35.3, 35.6, 52.7, 62.9, 79.8, 104.8, 132.7, 137.9, 169.2, 172.9; MS367.1 m/z (M+1).

Example 6 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1-ethyl-Propyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid [1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide wascoupled with (3,5-Difluoro-phenyl)-acetic acid to provide the titlecompound: C13 NMR (100 MHz, CDCl3) 10.7, 10.8, 13.9, 18.9, 28.8, 36.1,43.0, 53.0, 62.9, 102.5, 102.7, 103.3, 104.5, 112.3, 112.4, 112.5,112.6, 132.9, 138.0, 138.9, 161.9, 164.3, 164.5, 169.2, 169.5; MS 407.23m/z (M+1).

Example 7 2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoicacid [1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid [1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide wascoupled with (3,5-Difluoro-phenyl)-hydroxy-acetic acid to provide thetitle compound: C13 NMR (100 MHz, CDCl3) 10.7, 13.7, 13.7, 19.0, 19.1,35.5, 35.7, 52.9, 53.2, 62.9, 73.4, 73.5, 103.4, 103.7, 105.0, 105.2,109.6, 109.8, 109.9, 110.1, 132.5, 132.6, 137.4, 137.5, 144.1, 161.7,161.9, 164.3, 169.2, 169.6, 171.8, 172.0; MS 423.21 m/z (M+1).

Example 82-(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-2-methyl-propionicacid methyl ester

2-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-2-methyl-propionic acidmethyl ester was coupled with (3,5-Difluoro-phenyl)-acetic acid toprovide the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 18.9, 26.1,26.2, 35.9, 43.0, 53.1, 53.3, 61.2, 102.5, 102.8, 103.0, 106.1, 112.3,112.4, 112.5, 112.6, 132.0, 137.6, 138.8, 161.8, 162.0, 164.3, 164.4,169.3, 169.4, 172.6; MS 437.20 m/z (M+1).

Example 92-(4-{2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoylamino}-imidazol-1-yl)-2-methyl-propionicacid methyl ester

2-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-2-methyl-propionic acidmethyl ester was coupled with (3,5-Difluoro-phenyl)-hydroxy-acetic acidto provide the title compound: C13 NMR (100 MHz, CDCl3) 13.7, 13.8,19.0, 19.1, 26.0, 35.3, 35.7, 53.0, 53.2, 53.3, 61.2, 61.3, 73.3, 73.4,103.5, 103.7, 106.1, 106.3, 109.6, 109.8, 110.1, 131.6, 131.8, 137.0,137.1, 144.0, 161.9, 164.3, 169.3, 169.6, 171.9, 172.0, 172.5; MS 453.20m/z (M+1).

Example 102-{4-[2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoylamino]-imidazol-1-yl}-2-methyl-propionicacid methyl ester

2-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-2-methyl-propionic acidmethyl ester was coupled with (S)-2-hydroxy-3,3-dimethyl-butyric acid toprovide the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 19.1, 26.1,26.2, 26.3, 35.3, 35.5, 52.6, 53.3, 61.1, 79.6, 106.1, 131.9, 137.5,169.6, 172.7, 173.1; MS 397.23 m/z (M+1).

Example 112-{4-[2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoylamino]-imidazol-1-yl}-2-methyl-propionicacid methyl ester

2-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-2-methyl-propionic acidmethyl ester was coupled with (S)-2-hydroxy-3-methyl-butyric acid toprovide the title compound: C13 NMR (100 MHz, CDCl3) 13.8, 15.9, 19.1,19.4, 26.1, 26.2, 32.1, 35.5, 52.6, 53.3, 61.2, 76.4, 106.1, 131.9,137.5, 169.6, 172.6, 173.9; MS 383.2 m/z (M+1).

Example 123-(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-propionylamino}-imidazol-1-yl)-3-methyl-butyricacid methyl ester

3-[4-(2-Amino-propionylamino)-imidazol-1-yl]-3-methyl-butyric acidmethyl ester was coupled with (3,5-Difluoro-phenyl)-acetic acid toprovide the title compound: C13 NMR (100 MHz, CDCl3) 19.6, 28.1, 28.2,3.0, 46.9, 49.1, 51.9, 56.4, 102.5, 102.8, 103.0, 105.1, 112.3, 112.5,112.6, 131.0, 137.9, 138.7, 164.3, 169.1, 170.0; MS 423.2 m/z (M+1).

Example 133-{4-[2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-propionylamino]-imidazol-1-yl}-3-methyl-butyricacid methyl ester

3-[4-(2-Amino-propionylamino)-imidazol-1-yl]-3-methyl-butyric acidmethyl ester was coupled with (S)-2-hydroxy-3,3-dimethyl-butyric acid toprovide the title compound: C13 NMR (100 MHz, CDCl₃) 19.2, 26.2, 28.1,28.2, 35.2, 47.1, 48.6, 51.9, 56.4, 79.7, 105.1, 112.4, 131.0, 137.7,169.7, 170.0, 173.0; MS 383.3 m/z (M+1).

Example 144-(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino}-pentanoylamino]-imidazol-1-yl)-piperidine-1-carboxylicacid tert-butyl ester

4-(4-Amino-imidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl esterwas coupled with (L)-2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoicacid to afford the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 18.9,28.6, 33.1, 36.0, 43.1, 53.0, 55.8, 80.2, 102.6, 102.9, 105.7, 112.3,112.5, 112.6, 131.4, 137.8, 154.6, 169.1, 169.4; MS 520.2 m/z (M+1).

Example 15 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide esterwas coupled with (3,5-Difluoro-phenyl)-acetic acid to provide the titlecompound: C13 NMR (100 MHz, CDCl3) 14.0, 18.9, 24.3, 24.8, 25.2, 26.6,35.8, 35.9, 43.2, 53.2, 56.0, 59.4, 67.2, 102.6, 102.9, 103.1, 105.5,112.4, 112.4, 112.5, 112.6, 131.6, 137.4, 138.7, 138.8, 161.9, 162.1,164.4, 164.5, 169.2, 169.2; MS m/z 462.2 (M+1).

Example 16 2-[2-(3-Trifluoromethyl-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide esterwas coupled with (3-trifluoromethylphenyl)-acetic acid to provide thetitle compound: C13 NMR (100 MHz, CDCl3) 13.9, 18.9, 24.2, 26.5, 35.9,43.2, 53.1, 55.9, 59.3, 67.1, 105.4, 124.1, 126.2, 129.2, 131.5, 132.9,136.2, 137.4, 169.3, 169.7; MS m/z 494.38 (M+1).

Example 17 2-[2-(3-Trifluoromethoxy-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-2-Pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide esterwas coupled with (3-trifluoromethoxyphenyl)-acetic acid to provide thetitle compound: C13 NMR (100 MHz, CDCl3) 13.8, 18.8, 24.2, 26.5, 35.7,43.2, 53.1, 55.9, 59.3, 67.1, 105.4, 119.7, 122.0, 127.9, 130.2, 131.3,137.3, 137.4, 169.2, 169.7; MS m/z 510.3 (M+1).

Example 18 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide wascoupled with (3,5-Difluoro-phenyl)-acetic acid to provide the titlecompound: C13 NMR (100 MHz, CDCl3) 14.0, 19.0, 25.8, 35.7, 43.1, 53.3,55.5, 59.7, 67.4, 68.6, 102.9, 105.4, 112.4, 112.6, 130.9, 136.7, 169.4,169.5; MS m/z 478.2 (M+1).

Example 19 2-[2-(3,5-Difluoro-Phenyl)-2-hydroxy-acetylamino]-pentanoicacid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide wascoupled with (3,5-Difluoro-phenyl)-hydroxy-acetic acid to afford thetitle compound: MS m/z 478.3 (M+1); Diastereomers were separated using aS,S-Whelk-O1 column (5 cm×25 cm), eluting with 70:30 heptane:iPrOH at aflow rate of 110 mL/min.

Example 20 2-[2-(3,5-Difluoro-Phenyl)-2-hydroxy-acetylamino]-pentanoicacid [1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid [1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide wascoupled with (3,5-Difluoro-phenyl)-hydroxy-acetic acid to afford thetitle compound: C13 NMR (100 MHz, CDCl3) 10.7, 13.7, 13.7, 19.0, 19.1,35.5, 35.7, 52.9, 53.2, 62.9, 73.4, 73.5, 103.4, 103.7, 105.0, 105.2,109.6, 109.8, 109.9, 110.1, 132.5, 132.6, 137.4, 137.5, 144.1, 161.7,161.9, 164.3, 169.2, 169.6, 171.8, 172.0; MS 423.21 m/z (M+1);Diastereomers separated using using Chiralpak AD column, elute 50:50heptane:ethanol; Flow Rate 275 mL/min.

Example 21 2-[2-(4-Phenyl-thiazol-2-yl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide wascoupled with (4-phenyl-thiazol-2-yl)-acetic acid to afford the titlecompound: C13 NMR (100 MHz, CDCl3) 13.9, 19.0, 24.2, 25.6, 26.6, 26.7,35.2, 40.3, 53.6, 55.9, 59.1, 67.2, 105.3, 113.2, 126.5, 128.4, 129.0,131.4, 134.2, 137.4, 155.5, 163.4, 167.3, 168.6; MS m/z 509.4 (M+1).

Example 22 2-[2-(3-Trifluoromethyl-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide wascoupled with (3-trifluoromethylphenyl)-acetic acid to afford the titlecompound: C13 NMR (100 MHz, CDCl3) 13.9, 18.9, 25.9, 35.9, 43.2, 53.1,55.5, 59.2, 67.4, 68.8, 105.3, 112.5, 124.1, 124.2, 126.2, 126.3, 129.3,131.7, 132.9, 136.1, 137.5, 169.3, 169.7; MS m/z 510.4 (M+1).

Example 23 2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide wascoupled with (S)-2-hydroxy-3-methyl-butyric acid to afford the titlecompound: C13 NMR (100 MHz, CDCl3) 12.7, 15.2, 18.4, 18.9, 22.8, 25.3,31.8, 33.9, 53.0, 56.8, 60.7, 63.3, 75.8, 107.5, 130.8, 131.1, 171.7,175.7; MS m/z 408.5 (M+1).

Example 24 2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide wascoupled with (S)-2-hydroxy-3,3-dimethyl-butyric acid to afford the titlecompound: C13 NMR (100 MHz, CDCl3) 12.7, 18.9, 22.8, 25.2, 25.4, 33.9,34.8, 53.0, 56.8, 60.5, 63.3, 79.0, 107.5, 131.2, 171.8, 174.8; MS m/z422.4 (M+1).

Example 25 2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid[1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide wascoupled with (S)-2-hydroxy-3-methyl-butyric acid to afford the titlecompound: 13C NMR (100 MHz, CDCl3) 13.9, 16.1, 19.1, 19.4, 25.9, 32.3,35.4, 52.8, 55.5, 59.2, 67.4, 68.8, 105.3, 131.3, 137.2, 169.4, 174.1;MS m/z 424.4 (M+1).

Example 26 2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoicacid [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide wascoupled with (3,5-Difluoro-phenyl)-hydroxy-acetic acid to afford thetitle compound: H1 NMR (400 MHz, CDCl₃) 0.8 (m, 3H), 1.40 (m, 2H), 1.48(s, 2H), 1.70, (m, 2H), 2.20 (m, 4H), 2.42, (m, 2H), 3.58 (m,4H), 4.80(m, 0.5H), 4.90 (m, 0.5H), 5.12 (m, 0.5H), 5.20 (m, 0.5H), 6.72 (m, 1H)7.08 (m, 2H), 7.39 (s, 0.5H) 7.40 (s, 0.5H), 7.46 (s, 0.5H), 7.47(s,0.5H); MS m/z 494.4 (M+1).

Example 27 2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid[1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide wascoupled with (S)-2-hydroxy-3,3-dimethyl-butyric acid to afford the titlecompound: C13 NMR (100 MHz, CDCl3) 13.9, 19.2, 25.9, 26.4, 35.2, 35.3,52.8, 55.5, 59.1, 67.5, 68.9, 80.0, 105.2, 131.3, 137.2, 169.1, 173.3;MS m/z 438.2 (M+1).

Example 28 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-4-methyl-pentanoicacid [1-(1,1-dimethyl-2-Pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-4-methyl-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide wascoupled with (3,5-Difluoro-phenyl)-acetic acid to provide the titlecompound: C13 NMR (100 MHz, CDCl3) 22.5, 22.9, 24.2, 25.0, 26.6, 26.7,42.9, 43.1, 51.9, 56.0, 59.3, 67.3, 102.9, 105.5, 112.3, 112.6, 131.9,137.4, 169.1, 169.4; MS m/z 476.3 (M+1).

Example 292-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-propionamide

2-Amino-N-[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-propionamidewas coupled with (3,5-Difluoro-phenyl)-acetic acid to provide the titlecompound: ¹H NMR (400 MHz) 1.41 (d, 3H), 1.51 (s, 6H), 1.48 (s, 4H),2.32 (s, 4H), 2.7 (s, 2H), 3.5 (s, 2H), 4.88-4.83 (m, 1H), 7.44 (d, 1H,J=1.4 Hz), 6.63-6.68 (m, 1H), 6.71-6.90 (M, 2h), 7.58 (d, 1H, J=1.7 Hz),11.8 (brs, 1H) MS m/z 434.2 (M+1).

Example 30(4-[2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino]-imidazol-1-yl)-aceticacid methyl ester

(4-Amino-imidazol-1-yl)-acetic acid methyl ester was coupled with2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid to afford thetitle compound: C13 NMR (100 MHz, CDCl3) 13.5, 19.1, 33.8, 42.3, 50.3,53.6, 54.5, 102.2, 102.5, 102.7, 109.9, 112.4, 112.6, 130.0, 131.4,139.0, 161.9, 164.2, 166.5, 171.4; MS m/z 409.1 (M+1).

Example 312-(4-[2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino]-2-methyl-imidazol-1-yl)-2-methyl-Propionicacid methyl ester

2-(4-Amino-2-methyl-imidazol-1-yl)-2-methyl-propionic acid methyl esterwas coupled with 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acidto afford the title compound: C13 NMR (100 MHz, CDCl3) 13.8, 14.7, 18.9,26.1, 26.7, 35.5, 42.9, 53.3, 61.1, 102.7, 105.3, 112.3, 112.5, 134.9,138.9, 140.9, 169.5, 169.7, 173.4; MS m/z 451.2 (M+1).

Example 32 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(2-methoxy-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(2-methoxy-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide was coupledwith (3,5-Difluoro-phenyl)-acetic acid to provide the title compound:H₁NMR (400 MHz, CDCl3) 0.85 (t, 3H, J=7), 1.3 (m, 2H), 1.54 (s, 6H),1.65 (m, 1H), 1.80 (m, 1H), 3.29 (s, 3H), 3.43 (s, 2H), 3.53 (s, 3H),4.76, (m, 1H), 6.56 (m, 1H), 6.71 (m, 1H), 6.81 (m, 2H), 7.44 (s, 1H),7.65 (s, 1H); MS m/z 423.3 (M+1).

Example 334-(4-{2-[2-(3,5-Difluoro-Phenyl)-acetylamino}-pentanoylamino]-imidazol-1-yl)-benzoicacid methyl ester

4-(4-Amino-imidazol-1-yl)-benzoic acid methyl ester was coupled with2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid to afford thetitle compound: C13 NMR (100 MHz, CDCl3) 14.0, 19.0, 35.8, 43.1, 52.6,53.3, 102.7, 103.0, 103.2, 106.1, 112.4, 112.6, 120.4, 129.2, 131.7,132.1, 138.6, 139.0, 140.6, 161.9, 162.1, 164.4, 166.2, 169.6, 169.8; MSm/z 471.2 (M+1).

Example 34 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{1-[1-(2,2-dimethyl-propyl)-Pyrrolidin-3-yl]-1H-imidazol-4-yl}-amide

1-[1-(2,2-Dimethyl-propyl)-pyrrolidin-3-yl]-1H-imidazol-4-ylamine wascoupled with 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid toafford the title compound: C13 NMR (100 MHz, CDCl3) 14.0, 18.9, 28.6,33.0, 33.4, 35.9, 43.1, 53.1, 55.7, 57.3, 63.5, 68.3, 102.6, 102.8,103.1, 106.6, 112.3, 112.5, 112.6, 132.1, 137.7, 138.8, 161.9, 164.5,169.1; MS m/z 476.2 (M+1).

The following Examples were prepared by methods analogous to thatdescribed above for General Procedure B, reductive amination procedure(a):

Example 353-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoylamino]-imidazol-1-yl}-butyricacid methyl ester

3-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-butyric acid methyl esterwas reacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to providethe title compound: MS m/z 449.3 (M+1).

Example 362-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoylamino]-imidazol-1-yl}-2-methyl-propionicacid methyl ester

2-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-2-methyl-propionic acidmethyl ester was reacted with6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to provide the titlecompound: C13 NMR (100 MHz, CD30H) 13.0, 18.1, 24.5, 25.4, 25.8, 27.5,32.8, 53.1, 53.2, 57.9, 64.7, 100.8, 101.1, 109.9, 110.4, 110.8, 115.8,128.4, 131.6, 132.3, 139.1, 139.3, 159.5, 160.2, 166.8, 171.2; MS 449.3m/z (M+1).

Example 372-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid [1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide wasreacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to provide thetitle compound: C13 NMR (100 MHz, CDCl₃) 10.9, 14.1, 14.2, 19.5, 19.6,28.2, 28.6, 28.7, 28.9, 29.6, 29.9, 36.5, 36.6, 51.9, 52.3, 60.1, 60.6,62.9, 100.7, 100.9, 101.2, 104.2, 110.5, 110.6, 110.8, 118.2, 118.5,132.4, 137.9, 138.0, 139.6, 139.9, 159.8, 162.1, 162.2, 172.2, 172.4; MS419.2 m/z (M+1).

Example 383-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoylamino]-imidazol-1-yl}-3-methyl-butyricacid methyl ester

3-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-3-methyl-butyric acidmethyl ester was reacted with6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to provide the titlecompound: C13 NMR (100 MHz, CDCl3) 14.1, 16.7, 19.5, 19.6, 28.2, 28.7,29.6, 29.8, 36.5, 47.2, 51.9, 52.1, 52.7, 56.3, 60.2, 60.9, 101.1,104.4, 110.6, 130.5, 137.7, 170.0; MS 463.3 m/z (M+1).

Example 39 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(2-isopropylamino-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide

2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide was reacted withisopropylamine to afford the title compound: C13 NMR (100 MHz, CDCl3)14.0, 18.9, 23.3, 26.5, 35.9, 43.2, 49.3, 53.2, 57.7, 59.0, 102.6,102.9, 103.1, 105.1, 112.4, 112.4, 112.5, 112.6, 131.7, 137.7, 138.7,161.9, 162.1, 164.4, 164.5, 169.1; MS m/z 450.2 (M+1).

Example 40 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-2-methylamino-ethyl)-1H-imidazol-4-yl]-amide

2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide was reacted withmethylamine to afford the title compound: C13 NMR (100 MHz, CDCl3) 13.9,19.0, 26.5, 26.6, 36.0, 37.2, 43.1, 46.0, 53.2, 58.8, 62.6, 102.6,102.8, 103.1, 105.1, 112.3, 112.6, 131.6, 137.8, 138.8, 162.0, 164.5,169.2, 169.3; MS m/z 422.2 (M+1).

Example 41 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(2-benzylamino-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide

2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide was reacted withbenzylamine to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.0,18.9, 26.4, 26.5, 36.0, 43.1, 53.2, 54.1, 59.0, 59.3, 102.6, 102.9,103.1, 105.2, 112.4, 112.6, 127.2, 128.2, 128.6, 131.7, 137.8, 138.8,140.3, 161.9, 164.4, 164.5, 169.2; MS m/z 498.1 (M+1).

Example 42 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{1-[2-(2,2-dimethyl-propylamino)-1,1-dimethyl-ethyl-1H-imidazol-4-yl}-amide

2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide was reacted with2,2-dimethyl-propylamine to afford the title compound: C13 NMR (100 MHz,CDCl3) 14.0, 18.9, 26.3, 26.4, 27.8, 32.1, 35.9, 43.1, 53.2, 59.3, 61.2,63.0, 102.6, 102.8, 103.1, 105.2, 112.3, 112.6, 131.7, 137.6, 138.8,162.0, 164.4, 164.5, 169.2, 169.3; MS m/z 478.2 (M+1).

Example 43 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(2-dimethylamino-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide

2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide was reacted withdimethylamine to afford the title compound: C13 NMR (100 MHz, CDCl3)14.0, 18.9, 26.1, 26.2, 35.9, 43.2, 47.9, 53.1, 59.3, 69.9, 102.9,105.4, 112.4, 112.6, 131.7, 137.5, 169.2; MS m/z 436.2 (M+1),

Example 44 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{1-[1,1-dimethyl-2-(1-phenyl-ethylamino)-ethyl]-1H-imidazol-4-yl]-amide

2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide was reacted with1-phenyl-ethylamine_to afford the title compound: C13 NMR (100 MHz,CDCl3) 14.0, 19.0, 24.9, 26.0, 27.0, 36.0, 43.2, 53.2, 57.9, 58.6, 58.9,102.6, 102.9, 103.1, 105.2, 112.4, 112.6, 112.6, 126.8, 127.1, 128.6,131.7, 137.8, 138.8, 145.7, 161.9, 164.4, 164.5, 169.3; MS m/z 512.3(M+1).

Example 45 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-3-morpholin-4-yl-propyl)-1H-imidazol-4-yl]-amide

2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-3-oxo-propyl)-1H-imidazol-4-yl]-amide was reacted withmorpholine_to afford the title compound: MS m/z 492.2 (M+1).

Example 46 2-[2-(3,5-Difluoro-Phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-3-pyrrolidin-1-yl-propyl)-1H-imidazol-4-yl]-amide

2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-3-oxo-propyl)-1H-imidazol-4-yl]-amide was reacted withpyrrolidine to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.0,18.9, 23.6, 28.4, 28.7, 36.0, 42.1, 43.2, 51.3, 53.1, 54.4, 57.5, 103.0,105.3, 112.4, 112.6, 131.2, 137.8, 169.0, 169.2. MS m/z 476.2 (M+1).

Example 472-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-Pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide wasreacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to provide thetitle compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.5, 19.6, 24.3, 26.6,26.7, 28.2, 28.3, 28.8, 28.9, 29.7, 29.8, 36.6, 36.6, 52.1, 52.6, 56.0,59.1, 59.1, 60.2, 60.8, 67.3, 100.8, 101.1, 101.3, 104.8, 110.5, 110.7,131.1, 137.4, 172.2, 172.4; MS m/z 474.3 (M+1).

Example 48 2-(5-Chloro-indan-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide wasreacted with 5-Chloro-indan-2-one to provide the title compound: C13 NMR(100 MHz, CDCl3) 14.2, 19.5, 24.3, 26.6, 26.7, 36.4, 39.3, 39.8, 40.0,40.4, 56.0, 59.1, 59.2, 61.4, 67.3, 104.8, 125.1, 125.2, 125.9, 126.0,126.9, 126.9, 131.2, 137.3, 140.1, 143.2, 143.6, 172.0; MS m/z 458.4(M+1).

Example 49 2-(Indan-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide wasreacted with 2-indanone to provide the title compound: C13 NMR (100 MHz,CDCl3) 14.2, 19.5, 24.3, 26.6, 26.7, 36.4, 39.9, 40.6, 56.0, 59.0, 61.4,67.3, 104.8, 124.9, 125.0, 126.7, 126.8, 131.2, 137.4, 141.2, 141.7,172.2; MS m/z 424.4 (M+1).

Example 502-(6-Fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide wasreacted with 6-Fluoro-3,4-dihydro-1H-naphthalen-2-one to provide thetitle compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.6, 19.6, 24.3, 26.6,28.1, 28.3, 29.2, 30.1, 35.9, 36.5, 36.6, 36.7, 53.2, 53.4, 56.0, 59.1,60.4, 60.7, 67.3, 104.7, 104.8, 112.9, 113.1, 114.8, 114.9, 115.0,115.1, 130.2, 130.7, 130.8, 130.8, 131.1, 137.3, 137.8, 138.1, 160.1,162.5, 172.5; MS m/z 456.4 (M+1).

Example 512-(6-Chloro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide wasreacted with 6-chloro-3,4-dihydro-1H-naphthalen-2-one to provide thetitle compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.6, 19.6, 24.3, 26.6,27.9, 28.0, 29.2, 30.0, 36.0, 36.5, 36.6, 36.9, 53.1, 53.3, 56.0, 59.1,60.5, 60.8, 67.3, 104.7, 126.1, 128.5, 128.7, 130.7, 130.8, 131.2,131.5, 131.6, 133.6, 137.3, 137.7, 138.0, 172.4; MS m/z 472.4 (M+1).

Example 522-(6,8-Dichloro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide wasreacted with 6,8-dichloro-3,4-dihydro-1H-naphthalen-2-one to provide thetitle compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.5, 19.6, 24.3, 26.6,26.6, 26.7, 28.5, 29.5, 34.0, 34.7, 36.6, 52.5, 53.2, 56.0, 59.1, 59.2,60.1, 60.8, 67.3, 104.8, 126.7, 127.2, 127.3, 131.1, 131.5, 131.7,131.8, 131.9, 135.3, 137.3, 139.7, 140.0, 172.2, 172.4; MS m/z 506.4,508.4 (M+1).

Example 532-(5,7-Dimethyl-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide wasreacted with 5,7-dimethyl-3,4-dihydro-1H-naphthalen-2-one to provide thetitle compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.5, 19.6, 21.0, 24.3,25.3, 25.6, 26.6, 29.7, 30.7, 36.6, 37.1, 38.0, 53.0, 53.3, 56.0, 59.1,60.4, 60.8, 67.3, 104.7, 127.9, 28.0, 128.6, 128.7, 131.1, 131.3, 131.6,134.6, 135.1, 135.2, 136.4, 137.3, 172.5, 172.6; MS m/z 466.5 (M+1).

Example 54 2-(1,2,3,4-Tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide wasreacted with 3,4-Dihydro-1H-naphthalen-2-one to provide the titlecompound: C13 NMR (100 MHz, CDCl₃) 14.2, 19.5, 19.6, 24.3, 26.6, 28.0,28.3, 29.5, 30.5, 36.5, 36.6, 36.7, 37.5, 53.3, 53.6, 56.0, 59.1, 60.4,60.8, 67.3, 104.7, 126.0, 126.1, 126.2, 128.8, 128.9, 129.5, 129.6,131.1, 134.8, 135.3, 135.9, 136.3, 137.3, 172.6; MS m/z 438.5 (M+1).

Example 552-(6-Isopropyl-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide wasreacted with 6-Isopropyl-3,4-dihydro-1H-naphthalen-2-one to provide thetitle compound: C13 NMR (100 MHz, CDCl₃) 14.2, 19.5, 19.6, 24.3, 26.6,26.7, 28.2, 28.5, 29.6, 30.6, 33.9, 36.4, 36.5, 37.3, 53.4, 53.8, 56.0,59.1, 60.4, 60.8, 67.3, 104.7, 124.2, 126.7, 126.8, 129.5, 129.6, 131.1,132.2, 132.7, 135.7, 136.0, 137.3, 146.7, 146.8, 172.5, 172.6; MS m/z480.5 (M+1).

Example 56 2-[2-(2-Fluoro-phenyl)-1-methyl-ethylamino]-pentanoic acid[1-(1,1-dimethyl-2-Pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide wasreacted with 1-(2-Fluoro-phenyl)-propan-2-one to provide the titlecompound: C13 NMR (100 MHz, CDCl3) 14.2, 19.0, 19.4, 20.2, 21.2, 24.3,26.6, 36.1, 36.5, 37.1, 37.3, 53.8, 54.3, 56.0, 59.0, 60.6, 61.2, 67.3,104.7, 115.4, 115.6, 124.1, 124.2, 126.1, 128.2, 128.2, 131.1, 131.8,131.9, 137.3, 162.7, 172.5; MS m/z 444.4 (M+1).

Example 572-[1-Methyl-2-(3-trifluoromethyl-phenyl)-ethylamino]-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide wasreacted with 1-(3-trifluoromethyl-phenyl)-propan-2-one to provide thetitle compound: C13 NMR (100 MHz, CDCl3) 14.0, 14.2, 19.1, 19.5, 20.0,21.1, 24.3, 26.6, 26.6, 36.1, 36.5, 43.5, 44.1, 54.6, 55.2, 56.0, 59.1,60.8, 61.1, 67.3, 104.6, 104.7, 123.4, 126.2, 129.0, 129.2, 131.1,133.0, 137.2, 140.1, 172.3; MS m/z 494.3 (M+1).

Example 582-(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide wasreacted with 5,7-Difluoro-3,4-dihydro-1H-naphthalen-2-one to provide thetitle compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.6, 19.6, 20.6, 24.3,26.6, 28.4, 29.3, 36.5, 36.6, 37.1, 52.6, 56.0, 59.1, 60.6, 67.2, 101.3,104.7, 111.2, 131.1, 172.3; MS m/z 474.4 (M+1).

Example 59 2-(6-Bromo-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoicacid [1-(1,1-dimethyl-2-Pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide wasreacted with 6-bromo-3,4-dihydro-1H-naphthalen-2-one to provide thetitle compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.6, 19.6, 24.3, 26.6,27.8, 28.0, 29.1, 30.0, 36.0, 36.5, 36.6, 36.9, 53.0, 53.1, 56.0, 59.1,59.1, 60.5, 60.7, 67.3, 104.7, 104.8, 119.6, 119.7, 129.0, 131.1, 131.1,131.5, 131.6, 133.7, 134.2, 127.3, 137.3, 138.2, 138.5, 172.4, 172.4; MSm/z 516.3, 518.3 (M+1).

Example 60 2-[2-(3,5-Difluoro-phenyl)-ethylamino]-pentanoic acid[1-(1,1-dimethyl-2-Pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide wasreacted with (3,5-Difluoro-phenyl)-acetaldehyde to provide the titlecompound: C13 NMR (100 MHz, CDCl3) 14.1, 19.4, 24.3, 26.7, 36.0, 36.4,50.0, 56.0, 59.1, 63.1, 67.2, 101.8, 102.1, 102.3, 104.8, 111.5, 111.8,131.2, 137.3, 143.5, 162.0, 162.1, 164.5, 164.6, 171.7; MS m/z 448.4(M+1).

Example 61 2-[2-(3,5-Difluoro-phenyl)-1-methyl-ethylamino]-pentanoicacid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide wasreacted with 1-(3,5-difluoro-phenyl)-propan-2-one to provide the titlecompound: C13 NMR (100 MHz, CDCl3) 14.0, 14.1, 19.2, 19.5, 20.1, 21.1,24.3, 26.6, 36.1, 36.6, 43.6, 44.1, 54.4, 54.9, 56.0, 59.1, 59.1, 60.9,61.1, 67.3, 101.8, 101.9, 102.0, 102.2, 102.3, 102.4, 104.7, 104.7,112.0, 112.1, 112.2, 112.3, 112.3, 112.4, 112.5, 131.1, 137.2, 137.3,143.1, 143.1, 161.8, 162.0, 164.3, 164.4, 172.1, 172.4; MS m/z 462.4(M+1).

Example 622-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1-ethyl-Propyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid [1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide wasreacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to provide thetitle compound: C13 NMR (100 MHz, CDCl3) 10.9, 14.1, 14.2, 19.5, 19.6,28.2, 28.6, 28.7, 28.9, 29.6, 29.9, 36.5, 36.6, 51.9, 52.3, 60.1, 60.6,62.9, 100.7, 100.9, 101.2, 104.2, 110.5, 110.6, 110.8, 118.2, 118.5,132.4, 137.9, 138.0, 139.6, 139.9, 159.8, 162.1, 162.2, 172.2, 172.4; MS419.2 m/z (M+1); Chiral Separation using Chiralpak AD column, elute85:15 heptane:ethanol; Flow Rate 275 mL/min.

Example 632-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-3-morpholin-4-yl-propyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-3-morpholin-4-yl-propyl)-1H-imidazol-4-yl]-amide wasreacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to provide thetitle compound: 13C NMR 14.2, 19.5, 19.6, 28.2, 28.3, 28.5, 28.6, 28.6,28.7, 28.8, 29.7, 29.8, 30.8, 36.5, 36.6, 39.8, 52.3, 52.7, 54.0, 57.2,57.3, 60.3, 60.8, 67.1, 100.8, 101.1, 101.3, 104.6, 104.7, 110.5, 110.6,110.8, 110.9, 130.5, 137.6, 137.7, 139.9, 159.7, 162.3, 172.3, 172.5; MSm/z 504.2 (M+1).

Example 642-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide wasreacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to provide thetitle compound: Diast #1 (RT 12 min) 14.2, 19.5, 2.9, 26.0, 28.2, 28.9,29.7, 36.5, 52.9, 55.5, 58.9, 60.9, 67.5, 68.9, 101.1, 104.5, 110.7,131.2, 137.4, 172.4; MS m/z 490.3 (M+1). Diast#2 (R_(T) 18 min)14.2,19.6, 25.9, 26.0, 28.3, 28.9, 29.6, 36.5, 52.5, 55.5, 58.8, 60.4, 67.5,68.9, 101.1, 104.5, 110.6, 131.2, 137.3, 172.2; MS m/z 490.3 (M+1).Chiral sep using a Kromasil TBB column, elute 95/5, heptane/IPA, flowrate 85 ml/min.

Example 65 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{1-[1,1-dimethyl-2-(1-Phenyl-ethylamino)-ethyl]-1H-imidazol-4-yl}-amide

2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide was reacted with1-phenyl-ethylamine to afford the title compound: C13 NMR (100 MHz,CDCl3) 13.9, 18.9, 24.9, 25.9, 26.9, 36.0, 43.1, 53.1, 57.9, 58.5, 58.9,102.6, 102.9, 103.1, 105.2, 112.3, 112.5, 112.6, 126.7, 127.1, 128.6,131.7, 137.7, 138.7, 145.7, 161.9, 164.4, 164.5, 169.2; MS m/z 512.3(M+1).

Example 662-(6,8-Dichloro-1.2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide wasreacted with 6,8-Dichloro-3,4-dihydro-1H-naphthalen-2-one to provide thetitle compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.5, 25.9, 26.0, 28.5,29.4, 34.0, 34.6, 36.5, 52.7, 53.4, 55.5, 58.9, 60.9, 67.5, 68.9, 104.6,126.7, 127.2, 127.3, 131.2, 131.4, 131.8, 137.4, 139.9.

Example 672-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-4-methyl-pentanoicacid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-4-methyl-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide wasreacted with 6,8-Dichloro-3,4-dihydro-1H-naphthalen-2-one to provide thetitle compound: MS m/z 448.4 (M+1).

Example 682-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-N-[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-propionamide

2-Amino-N-[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-propionamidewas reacted with 6,8-Dichloro-3,4-dihydro-1H-naphthalen-2-one to providethe title compound: C13 NMR (100 MHz, CDCl3) 20.5, 24.2, 26.6, 28.2,28.9, 29.0, 29.5, 29.7, 51.9, 52.3, 55.5, 56.0, 56.0, 59.1, 59.1, 67.2,100.7, 101.0, 101.2, 104.8, 110.6, 110.8, 118.1, 131.1, 137.3, 139.9,159.8, 162.3, 172.5,172.6; MS m/z 446.2 (M+1).

Example 692-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(2-dimethylamino-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide

2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide was reacted withdimethyl amine to afford the title compound: C13 NMR (100 MHz, CDCl3)14.2, 19.5, 19.6, 26.2, 26.2, 26.3, 28.2, 28.3, 28.8, 29.6, 29.8, 36.6,48.0, 52.3, 52.8, 58.9, 59.0, 60.3, 60.8, 70.0, 101.0, 104.6, 110.7,131.2, 137.3, 159.8, 162.2, 172.4, 183.1, 183.9; MS m/z 448.4 (M+1).

Example 704-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoylamino]-imidazol-1-yl}-benzoicacid methyl ester

4-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-benzoic acid methyl esterwas reacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to providethe title compound: MS m/z 483.2 (M+1).

Example 712-(6,8-Difluoro-1,1-dimethyl-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoicacid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide wasreacted with 6,8-Difluoro-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-oneto afford the title compound: C13 NMR (100 MHz, CDCl3) 14.3, 19.4, 19.7,22.5, 23.0, 24.3, 24.8, 26.3, 26.6, 27.4, 27.5, 29.7, 36.4, 37.1, 38.0,45.8, 47.6, 56.0, 59.2, 60.7, 62.5, 63.0, 65.5, 67.3, 104.7, 104.8,111.0, 110.2, 112.5, 131.1, 131.2, 137.2, 172.2; MS m/z 502.3. (M+1).

Example 722-(6-Isopropyl-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1 dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

2-Amino-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide wasreacted with 6-Isopropyl-3,4-dihydro-1H-naphthalen-2-one to afford thetitle compound: C13 NMR (100 MHz, CDCl3) 14.1, 19.5, 19.6, 24.2, 26.6,26.7, 28.2, 28.4, 29.6, 30.6, 33.9, 36.3, 36.5, 37.2, 53.4, 53.7, 56.0,59.1, 60.3, 60.8, 67.3, 104.6, 124.1, 126.7, 126.8, 129.5, 129.6, 131.1,132.1, 135.7, 136.0, 137.3, 146.7, 146.8, 172.4, 172.6; MS m/z 480.5(M+1).

The following examples were prepared using General procedure I:

Example 732-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(2-hydroxy-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide

2-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoylamino]-imidazol-1-yl}-2-methyl-propionicacid methyl ester was reduced using LAH to afford the title compound:mixture of diasteromers C13 NMR (100 MHz, CDCl3) 14.1, 14.2, 14.4, 19.4,19.5, 21.2, 22.7, 24.7, 24.8, 24.9, 28.1, 28.3, 28.8, 28.9, 29.6, 29.7,36.4, 52.1; 52.7, 59.3, 60.0, 60.6, 60.7, 70.5, 100.8, 101.0, 101.3,104.6, 110.5, 110.6, 110.7, 110.8, 117.9, 118.1, 118.4, 118.6, 131.2,131.3, 137.3, 137.4, 139.5, 139.6, 139.7, 139.8, 139.9, 139.9, 159.7,159.8, 159.9, 162.1, 162.2, 162.3, 172.4, 172.6; MS m/z 421.4 (M+1).

Example 74 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(2-hydroxy-ethyl)-1H-imidazol-4-yl]-amide

(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-aceticacid methyl ester was reduced using LAH to afford the title compound:C13 NMR (100 MHz, CDCl3) 12.8, 19.0, 34.3, 41.6, 49.8, 53.6, 61.1,101.6, 101.8, 102.1, 108.4, 111.9, 112.1, 112.1, 134.0, 136.6, 162.0,164.5, 170.3, 171.4; MS m/z 381.1 (M+1).

Example 75 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(2-hydroxy-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide

2-(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-2-methyl-propionicacid methyl ester was reduced with LAH to afford the title compound: C13NMR (100 MHz, CDCl3) 13.9, 18.9, 24.7, 24.8, 35.5, 42.8, 53.2, 59.5,70.1, 102.5, 102.8, 103.0, 105.6, 112.3, 112.4, 112.5, 112.6, 131.8,137.1, 138.6, 138.7, 161.8, 161.9, 164.3, 164.4, 169.4, 169.8; MS 409.2m/z (M+1).

Example 76 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(3-hydroxy-1,1-dimethyl-propyl)-1H-imidazol-4-yl]-amide

3-(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-3-methyl-butyricacid methyl ester was reduced to afford the title compound: C13 NMR (100MHz, CDCl3) 14.0, 18.9, 26.2, 28.8, 29.3, 36.1, 43.1, 44.9, 53.1, 57.5,58.2, 103.1, 105.2, 112.3, 112.6, 131.5, 137.7, 168.9, 169.7; MS 423.2m/z (M+1).

Example 77 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(1-piperidin-4-yl-1H-imidazol-4-yl)-amide

4-(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-piperidine-1-carboxylicacid tert-butyl ester (1.1 g, 2.1 mmole) was dissolved in 20 mL ofmethylene chloride and 1.6 mL of trifluoroacetic acid was added.Reaction stirred overnight, extrated with sodium bicarbonate, and usedwithout further purification to afford the title compound: C13 NMR (100MHz, CDCl3) 12.8, 18.9, 29.9, 34.1, 41.5, 43.2, 52.4, 53.7, 101.8,105.6, 111.9, 112.1, 132.0, 137.1, 170.4, 171.5; MS 420.1 m/z (M+1).

Example 78 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1-methyl-piperidin-4-yl)-1H-imidazol-4-yl]-amide

2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(1-piperidin-4-yl-1H-imidazol-4-yl)-amide (200 mg, 4.8 mmol) wasdissolved in 5 mL of THF and 0.5 mL of water and 0.04 mL of 38%formaldehyde and 0.06 mL of formic acid was added. The reaction washeated for 12h at 800C. The solution was extracted with methylenechloride and sodium bicarbonate. The resultant organics wereconcentrated and purified by silica gel chromatography to afford thetitle compound: C13 NMR (100 MHz, CDCl3) 13.9, 18.9, 33.3, 36.0, 43.1,46.1, 53.0, 54.7, 55.3, 102.6, 102.9, 103.1, 105.9, 112.3, 112.6, 131.5,137.7, 138.7, 162.0, 164.5, 169.2; MS432.2 m/z (M+1).

Example 79 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1-acetyl-piperidin-4-yl)-1H-imidazol-4-yl]-amide

2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(1-piperidin-4-yl-1H-imidazol-4-yl)-amide (200 mg, 4.8 mmol) wasdissolved in 5 mL of methylene chloride, charged with 0.08 mL oftriethylamine, and 0.03 mL of acetylchloride at 0° C. The reaction wasstirred for 12h, quenched with sodium bicarbonate, extrated withmethylene chloride and concentrated. The compound was purified by silicagel chromatography to afford the title compound: C13 NMR (100 MHz,CDCl3) 13.9, 18.9, 21.6, 32.8, 33.7, 36.0, 40.7, 43.0, 45.4, 53.1, 55.5,102.6, 102.8, 103.1, 105.6, 105.7, 112.3, 112.4, 112.5, 131.5, 137.8,169.1, 169.3, 169.5; MS 462.25 m/z (M+1).

Example 80 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid1-[1-(3,3-dimethyl-butyryl)-piperidin-4-yl]-1H-imidazol-4-yl)-amide

Following the procedure for Example 21;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(1-piperidin-4-yl-1H-imidazol-4-yl)-amide was coupled witht-butylacetylchloride to afford the title compound: C13 NMR (100 MHz,CDCl3) 13.9, 18.9, 30.2, 31.6, 33.0, 33.8, 36.0, 40.6, 43.0, 44.9, 45.7,53.0, 55.7, 102.6, 102.8, 103.1, 105.8, 112.3, 112.4, 112.5, 112.6,131.5, 137.8, 138.8, 138.9, 161.8, 162.0, 164.3, 164.5, 169.3, 169.5,170.6; MS 518.30 m/z (M+1).

Example 81 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{1-[1-(3,3-dimethyl-butyl)-piperidin-4-yl]-1H-imidazol-4-yl}-amide

2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(1-piperidin-4-yl-1H-imidazol-4-yl)-amide (100 mg, 2.4 mmol) was chargedwith 1 mL of THF, 1 mL of Dichloroethane, 0.06 mL of triethyamine, 0.03mL of 3,3-dimethylbutyraldehyde, and 63 mg ofsodiumtriacetoxyborohydride. The reaction was stirred overnight,quenched with sodiumbicarbonate, extracted with methylene chloride, andthe resultant oil purified by silica gel chromatography to afford thetitle compound: C13 NMR (100 MHz, CDCl3) 13.9, 18.8, 29.7, 29.9, 33.3,36.0, 40.9, 43.1, 52.9, 53.1, 54.5, 55.9, 102.8, 103.1, 105.9, 112.3,112.4, 112.5, 112.6, 131.5, 137.6, 169.2; MS 504.3 m/z (M+1).

Example 82 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{1-[1-(2,2-dimethyl-propyl)-piperidin-4 yl]-1H-imidazol-4-yl}-amide

Following the procedure for Example 81;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(1-piperidin-4-yl-1H-imidazol-4-yl)-amide was reacted withtrimethylacetaldehyde to afford the title compound: C13 NMR (100 MHz,CDCl3) 14.0, 18.8, 27.8, 30.5, 33.3, 33.8, 36.0, 43.1, 53.1, 53.3, 55.9,69.6, 102.6, 102.9, 103.1, 105.8, 112.3, 112.6, 131.5, 137.6, 138.7,162.0, 164.4, 169.2; MS 490.3 m/z (M+1).

Example 832-[6-(4-Fluoro-phenyl)-1,2,3,4-tetrahydro-naphthalen-2-ylamino]-pentanoicacid [1-(1,1-dimethyl-2-Pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

2-(6-Bromo-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide (1equiv) is dissolved in 3:1 dimethoxyethane:water and Pd(PPh₃)₄ (0.03equiv.) and sodium carbonate (3 equiv) is added and the reaction heatedat 90° C. overnight. The reaction is cooled, water added, and extractedwith methylene chloride. The solvent is dried, concentrated and theresidue purified by silica gel chromatography to provide the titlecompound: MS m/z 532.5 (M+1).

Example 842-[(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-methyl-amino]-pentanoicacid [1-(1,1-dimethyl-2-Pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide (1equiv) is dissolved in methanol and to the reaction is added formalin (4equiv) and sodium cyanoborohydride (2.0 equiv). The reaction is stirredat rt for 3h, quenched with water, and extracted with methylenechloride. The solvent is dried, concentrated and the residue purified bysilica gel chromatography to provide the title compound: Diagnostic C13NMR (100 MHz, CDCl3) 55.9, 57.0, 57.1, 56.0, 65.1, 67.2, 101.0, 104.5,110.5, 110.7, 131.1; MS m/z 488.4 (M+1).

Example 85 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[7-(2,2-dimethyl-provyl)-5,5-dimethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-1-yl]-amide

{1-[1-(1,1-Dimethyl-2-oxo-ethyl)-1H-imidazol-4-ylcarbamoyl]-butyl}-carbamicacid tert-butyl ester (1 equiv) was combined with 2,2-dimethyl propylamine (2 equiv), 4A molecular sieves, and methylene chloride. To thereaction is added sodium borohyrdride (1 equiv) and the reaction stirredfor 3h, quenched with sodium bicarbonate, and extracted with methylenechloride. The solvent is dried, concentrated and the residue purified bysilica gel chromatography to provide the title compound:

To the above amine (1 equiv) in 9:1 THF:water is added formalin (1.1equiv) and formic acid (2 equiv) and the reaction heated to 80° C. for5h. The reaction was quenched with sodium bicarbonate and extracted withmethylene chloride. The solvent is dried, concentrated and the residuepurified by silica gel chromatography to provide{1-[7-(2,2-dimethyl-propyl)-5,5-dimethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-1-ylcarbamoyl]-butyl}-carbamicacid tert-butyl ester.

Following general procedure D, deprotection afforded 2-Amino-pentanoicacid[7-(2,2-dimethyl-propyl)-5,5-dimethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-1-yl]-amide

Following general coupling procedure A, 2-amino-pentanoic acid[7-(2,2-dimethyl-propyl)-5,5-dimethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-1-yl]-amideis coupled with (3,5-difluoro-phenyl)-acetic acid to provide the titlecompound: Diagnostic C13 NMR (100 MHz, CDCl3) 13.5, 18.9, 27.4, 28.1,28.6, 33.5, 35.4, 43.1, 52.8, 53.2, 56.2, 65.7, 69.9, 102.9, 112.3,112.6, 117.4, 129.2, 169.9; MS m/z 490.5 (M+1).

Example 862-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid{1-[2-(2,2-dimethyl-propylamino)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-amide

Combine L-norvaline methyl ester-hydrochloride (1 equiv) with6,8-difluoro-3,4-dihydro-1H-naphthalen-2-one (1 equiv) in methylenechloride and stir 30 min. and add sodium triacetoxy borohydride (1.1equiv) and stir at rt overnight. The reaction is quenched with aqueoussodium bicarbonate, extracted with methylene chloride, dried, andconcentrated. The resultant material is purified by silica gelchromatography to afford the separated diastereomers of2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acidmethyl ester: Diastereomer 1; 13C NMR (100 MHz, CDCl3) 14.0, 19.4, 27.7,28.2, 29.5, 29.6, 36.3, 51.1, 58.7, 100.7, 100.9, 101.2, 110.5, 110.7,110.8, 118.5, 118.6, 141.1, 159.7, 159.8, 162.1, 176.7; MS m/z 298.3(M+1). Diastereomer 2; Diagnostic ¹³C NMR (100 MHz, CDCl3) 14.0, 19.3,28.3, 28.4, 28.5, 30.3, 36.4, 51.1, 52.0, 58.5, 100.7, 100.9, 101.2,110.5, 110.7, 176.8; MS m/z 298.3 (M+1).

2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acidmethyl ester (1 equiv) is dissolved in THF:water (5:1) and LiOH (1.2equiv) is added. The reaction is stirred overnight at rt, the solvent isremoved, water added, and the pH is adjusted to 7 using 1 N hydrochloricacid. The solid is filtered, washed with water and diethyl ether, anddried to afford2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid;Acid derived from diasteromer 1: H1 NMR (400 MHz, CD₃OD) 0.99 (t, 3H,J=7.5), 1.48 (m, 2H), 1.82 (m, 3H), 2.36 (m, 1H), 2.65 (m, 1H), 2.95 (m,2H), 3.28 (s, 1H), 3.42 (m, 1H), 3.74 (m, 1H), 6.80 (m, 2H); (MS m/z284.3 (M+1). Acid derived from diasteromer 2: H1 NMR (400 MHz, CD₃OD)0.94 (t, 3H, J=7.6), 1.42 (m, 2H), 1.56 (m, 3H), 1.96 (m, 1H), 2.25 (m,1H), 2.85 (m, 3H), 3.15 (m, 1H), 3.25 (m, 1H), 6.64 (m, 2H); MS m/z284.2 (M+1).

Combine2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid(1 equiv) derived from diasteromer #2 above, TPTU (1 equiv),diisopropylethylamine (2 equiv) in DMF followed by1-[2-(2,2-dimethyl-propylamino)-1,1-dimethyl-ethyl]-1H-imidazol-4-ylamine(2 equiv) in methylene chloride. The reaction is stirred overnight atrt, quenched with aq. sodium bicarbonate, and extracted with methylenechloride. The solvent is dried, concentrated, and purified by silica gelchromatography to afford diastereomer #2 of the title compound: C13 NMR(100 MHz, CDCl3) 14.1, 19.5, 26.4, 27.8, 28.2, 28.9, 29.8, 32.1, 36.6,38.8, 52.8, 59.1, 60.9, 61.3, 63.0, 100.8, 101.0, 101.3, 104.5, 110.6,110.8, 110.9, 131.2, 137.6, 139.8, 159.8, 172.4; MS m/z 490.2 (M+i).

Combine2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid(1 equiv) derived from diasteromer #1 above, TPTU (1 equiv),diisopropylethylamine (2 equiv) in DMF followed by1-[2-(2,2-dimethyl-propylamino)-1,1-dimethyl-ethyl]-1H-imidazol-4-ylamine(2 equiv) in methylene chloride. The reaction is stirred overnight atrt, quenched with aq. sodium bicarbonate, and extracted with methylenechloride. The solvent is dried, concentrated, and purified by silica gelchromatography to afford diastereomer #1 of the title compound.

Example 872-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-Dentanoic acid[1-(1,1-dimethyl-2-Piperidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

Following the procedure for Example 86,2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid(diastereomer 2) was reacted with1-(1,1-Dimethyl-2-piperidin-1-yl-ethyl)-1H-imidazol-4-ylamine to affordthe title compound: C13 NMR (100 MHz, CDCl3) 14.1, 19.5, 24.1, 25.8,25.9, 26.7, 28.2, 28.9, 29.8, 36.6, 38.8, 52.8, 56.8, 59.1, 60.9, 69.1,100.8, 101.0, 101.3, 104.6, 110.7, 110.8, 118.2, 131.3, 137.2, 139.9,172.3; MS m/z 488.3 (M+1).

Example 882-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(2-dimethylamino-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide

Following the procedure for Example 86,2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid(diastereomer 2) was reacted with1-(2-Dimethylamino-1,1-dimethyl-ethyl)-1H-imidazol-4-ylamine to affordthe title compound: C13 NMR (100 MHz, CDCl3) 14.1, 19.5, 26.2, 28.2,28.8, 28.9, 29.8, 36.6, 48.0, 52.8, 59.0, 60.9, 70.0, 100.8, 101.1,101.3, 104.6, 110.7, 110.8, 131.3, 137.4, 172.3; MS m/z 448.3 (M+1).

Example 892-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid{1-[1,1-dimethyl-2-(2,2,2-trifluoro-ethylamino)-ethyl]-1H-imidazol-4-yl}-amide

Following the procedure for Example 86,2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid(diastereomer 2) was reacted with1-[1,1-Dimethyl-2-(2,2,2-trifluoro-ethylamino)-ethyl]-1H-imidazol-4-ylamineto afford the title compound: C13 MR (100 MHz, CDCl3) 14.1, 19.5, 26.0,28.2, 28.8, 29.8, 36.6, 38.8, 50.5, 50.8, 51.1, 51.4, 52.7, 58.6, 58.7,60.8, 100.8, 101.0, 101.3, 104.3, 110.7, 110.8, 110.9, 118.0, 118.1,124.2, 127.0, 131.2, 138.0, 139.8, 159.9, 172.6; MS m/z 502.2 (M+1).

Example 902-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

Following the procedure for Example 86,2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid(diastereomer 2) was reacted with1-(1,1-Dimethyl-2-pyrrolidin-1-yl-ethyl)₄-nitro-1H-imidazole to affordthe title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.5, 24.3, 26.6,28.2, 28.8, 28.9, 29.8, 36.6, 52.8, 56.0, 59.1, 60.9, 67.3, 100.8,101.1, 101.3, 104.8, 110.7, 110.9, 112.5, 131.2, 137.3, 172.4; MS m/z474.3 (M+1).

Example 912-(6,8-Difluoro-1.2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

Following the procedure for Example 86,2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid(diastereomer 1) was reacted with1-(1,1-Dimethyl-2-pyrrolidin-1-yl-ethyl)-4-nitro-1H-imidazole to affordthe title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.6, 24.3, 26.6,28.2, 28.6, 29.6, 36.6, 51.9, 56.0, 59.3, 60.3, 67.2, 100.8, 101.0,101.3, 104.9, 110.7, 112.5, 130.8, 172.6; MS m/z 474.3 (M+1).

Example 922-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(3-hydroxy-cyclobutyl)-1H-imidazol-4-yl]-amide

Following the procedure for Example 86,2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid(diastereomer 2) was reacted with 3-(4-Amino-imidazol-1-yl)-cyclobutanolto afford the title compound: C13 NMR (100 MHz, CDCl₃) 14.1, 19.5, 28.2,28.9, 29.7, 36.5, 40.2, 41.9, 43.4, 48.7, 52.9, 60.5, 60.9, 64.5, 100.8,101.1, 101.3, 105.1, 105.3, 110.7, 110.9, 131.6, 131.9, 137.7, 139.8,159.8, 162.3, 172.6; MS m/z 419.2 (M+1).

Example 932-(6,8-Difluoro-1.2.3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid{1-[2-(2,6-dimethyl-morpholin-4-yl)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-amide

Following the procedure for Example 86,2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid(diastereomer 2) was reacted with1-[2-(2,6-Dimethyl-morpholin-4-yl)-1,1-dimethyl-ethyl]-1H-imidazol-4-ylamineto afford the title compound: C13 NMR (100 MHz, CDCl3) 14.1, 19.1, 19.5,25.9, 28.2, 28.9, 29.7, 36.6, 38.8, 53.0, 58.9, 61.0, 61.3, 68.5, 72.1,74.4, 76.9, 77.3, 77.6, 100.8, 101.1, 101.3, 104.7, 110.7, 110.9, 117.9,131.2, 137.3, 139.8, 159.8, 162.3, 172.3; MS m/z518.2 (M+1).

Example 942-(6,8-Difluoro-1.2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid(1-[2-[(2,2-dimethyl-propyl)-methyl-amino]-1,1-dimethyl-ethyl]-1H-imidazol-4-yl)-amide

Following the procedure for Example 86,2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid(diastereomer 2) was reacted with1-{2-[(2,2-Dimethyl-propyl)-methyl-amino]-1,1-dimethyl-ethyl}-1H-imidazol-4-ylamineto afford the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.5, 26.8,28.2, 28.8, 28.9, 29.8, 33.4, 36.6, 46.6, 52.8, 59.4, 59.5, 60.9, 72.4,74.2, 101.1, 104.8, 106.9, 110.7, 110.9, 118.0, 131.1, 137.4, 139.3,139.8, 162.2, 172.4, 194.6; MS m/z 504.4 (M+1).

Example 952-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid{1-[1,1-dimethyl-2-(4-methyl-piperazin-1-yl)-ethyl]-1H-imidazol-4-yl}-amide

Following the procedure for Example 86,2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid(diastereomer 2) was reacted with1-[1,1-Dimethyl-2-(4-methyl-piperazin-1-yl)-ethyl]-1H-imidazol-4-ylamineto afford the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.5, 25.8,25.9, 28.2, 28.9, 29.7, 36.5, 46.1, 52.9, 55.0, 55.7, 59.0, 60.9, 68.2,101.1, 101.3, 104.5, 110.9, 131.3, 137.3, 172.3; MS m/z503.3 (M+1).

Example 96 2-[2-(3,5-Difluoro-Phenyl)-acetylamino]-pentanoic acid[1-(2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide

2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(2-hydroxy-ethyl)-1H-imidazol-4-yl]-amide (1 equiv) was dissolved inpyridine and treated with methansulfonyl chloride (2.2 equiv) at 0° C.The reaction was warmed to rt and stirred for 4h, quenched with sodiumbicarbonate, and extracted with methylene chloride. The extracts weredried and concentrated to provide methanesulfonic acid2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-ethylester which was used without further purification.

Methanesulfonic acid2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-ethylester (1 equiv) was dissolved in acetonitrile and treated with potassiumcarbonate (1.5 equic) and morpholine (3 equiv). The reaction was heatedto 65° C. for 18h and quenched with water, extracted with methylenechloride, dried, and concentrated. The residue was purified by columnchromatography to afford the title compound: C13 NMR (100 MHz, CDCl3)14.0, 18.9, 36.0, 43.1, 45.1, 53.1, 53.9, 58.9, 67.1, 102.6, 102.9,107.9, 112.3, 112.6, 133.5, 137.6, 139.0, 161.0, 162.0, 169.3, 169.4; MSm/z 450.1 (M+1).

Example 97 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{1-[2-(2,2-dimethyl-propylamino)-ethyl]-1H-imidazol-4-yl}-amide

The title compound was prepared following the procedure shown forExample 96 using 2,2-dimethyl-propylamine to afford the title compound:C13 NMR (100 MHz, CDCl3) 14.0, 18.8, 27.8, 31.8, 35.9, 43.1, 47.9, 50.9,53.2, 62.0, 102.9, 107.7, 112.3, 112.6, 133.5, 137.7, 169.3; MS m/z450.2 (M+1).

Example 98 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{1-[2-(4-methyl-piperazin-1-yl)-ethyl]-1H-imidazol-4-yl}-amide

The title compound was prepared following the procedure shown forExample 96 using N-methyl piperazine to afford the title compound: C13NMR (100 MHz, CDCl3) 14.0, 18.9, 36.0, 43.1, 45.4, 46.1, 53.1, 53.4,55.1, 58.4, 102.8, 107.9, 112.3, 112.6, 133.5, 137.5, 139.0, 162.0,164.3, 169.3, 169.5; MS m/z 463.3. (M+1).

Example 99 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(2-hydroxy-1,1,2-trimethyl-propyl)-1H-imidazol-4-yl]-amide

To a solution of2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-2-methyl-propionicacid methyl ester (1 equiv) in tetrahydrofuran at −78° C. is addedmethyllithium-lithium bromide (5 equiv., 1.5 M in ether) dropwise. Thereaction is stirred for 30 min., quenched with water, and extracted withmethylene chloride. The solvent is dried, concentrated, and purified bysilica gel chromatography to afford the title compound: C13 NMR (100MHz, CDCl3) 14.0, 18.9, 24.3, 25.2, 26.0, 35.9, 42.9, 53.1, 64.7, 74.4,102.8, 107.2, 112.4, 112.6, 133.3, 136.3, 169.0, 169.2; MS m/z 437.3(M+1).

Example 100 2-[2-(3,5-Difluoro-Phenyl)-acetylamino]-pentanoic acid[1-(3-hydroxy-1,1,3-trimethyl-butyl)-1H-imidazol-4-yl]-amide

Following the procedure of Example 99,3-(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-3-methyl-butyricacid methyl ester was reacted with methyllithium-lithium bromide toafford the title compound: C13 NMR (100 MHz, CDCl3) 14.0, 18.9, 29.9,30.3, 31.5, 36.0, 43.1, 53.1, 53.7, 58.2, 70.9, 102.9, 105.6, 112.3,112.6, 131.7, 137.5, 138.5, 164.4, 169.1, 169.3; MS m/z 451.2 (M+1).

Example 101 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(2-ethyl-2-hydroxy-1,1-dimethyl-butyl)-1H-imidazol-4-yl]-amide

To a solution of2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-2-methyl-propionicacid methyl ester (1 equiv) in tetrahydrofuran at −0° C. is added ethyllithium (5 equiv., 0.5 M benzene/cyclohexane) dropwise. The reaction isstirred for 30 min., quenched with water, and extracted with methylenechloride. The solvent is dried, concentrated, and purified by silica gelchromatography to afford the title compound: C13 NMR (100 MHz, CDCl3)9.0, 9.3, 14.0, 18.9, 24.5, 25.2, 27.3, 27.5, 36.0, 43.0, 53.1, 65.9,102.5, 102.8, 103.0, 107.2, 112.4, 112.6, 112.7, 133.3, 136.3, 138.6,164.3, 164.5, 169.0, 169.1; MS m/z 465.3 (M+1).

Example 102 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(3-ethyl-3-hydroxy-1,1-dimethyl-pentyl)-1H-imidazol-4-yl]-amide

Following the procedure of Example 101,3-(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-3-methyl-butyricacid methyl ester was reacted with ethyl lithium to afford the titlecompound: C13 NMR (100 MHz, CDCl3) 7.9, 8.2, 14.0, 18.8, 29.9, 30.7,31.5, 32.2, 36.0, 43.1, 49.2, 53.1, 58.2, 75.1, 102.9, 103.1, 105.5,112.3, 112.6, 131.8, 137.4, 162.0, 168.9, 169.2; MS m/z 479.3 (M+1).

Example 103

The following compounds are prepared utilizing the procedures describedabove.

-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    (1-tert-butyl-1H-imidazol-4-yl)-amide;-   2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid    (1-tert-butyl-1H-imidazol-4-yl)-amide;-   2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid    (1-tert-butyl-1H-imidazol-4-yl)-amide;-   2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid (1-tert-butyl-1H-imidazol-4-yl)-amide;-   2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-N-(1-isopropyl-1H-imidazol-4-yl)-propionamide;-   2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid    (1-isopropyl-1H-imidazol-4-yl)-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    {1-[2-(3-hydroxy-pyrrolidin-1-yl)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    {1-[1-(2,2-dimethyl-propyl)-azetidin-3-yl]-1H-imidazol-4-yl}-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    {1-[1-(2,2-dimethyl-propionyl)-azetidin-3-yl]-1H-imidazol-4-yl}-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(2-isopropoxy-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(6,8-Difluoro-1,2,3,4-tetrahydro-1,4-methano-naphthalen-2-ylamino)-pentanoic    acid    [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(5,7-Difluoro-chroman-3-ylamino)-pentanoic acid    [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(4,6-Difluoro-tricyclo[6.2.2]dodeca-2(7),3,5-trien-9-ylamino)-pentanoic    acid    [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(Naphthalen-2-ylamino)-pentanoic acid    [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(Quinolin-3-ylamino)-pentanoic acid    [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(1-Methyl-1H-indol-3-ylamino)-pentanoic acid    [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-2-trifluoromethyl-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-2-fluoro-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-2-phenyl-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-5-phenyl-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-5-trifluoromethyl-1H-imidazol-4-yl]-amide;-   5-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-3-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-3H-imidazole-4-carboxylic    acid methyl ester;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    (6,6-dimethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-1-yl)-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    (6-methyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    (3,4-dihydro-2H-imidazo[5, 1-b][1,3]oxazin-8-yl)-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    (1H-imidazo[1,2-a]pyridin-3-yl)-amide;-   2-[2-(3,5-Difluoro-phenyl)-ethylamino]-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-ethylamino]-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-1-methyl-ethylamino]-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(3,5-Difluoro-benzylamino)-pentanoic acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;-   2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid [1-(1-dimethylaminomethyl-cyclopentyl)-1H-imidazol-4-yl]-amide;    and-   2-(6,8-Difluoro-1-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic    acid    [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide

The invention described and claimed herein is not to be limited in scopeby the specific embodiments herein disclosed, since these embodimentsare intended as illustrations of several aspects of the invention. Anyequivalent embodiments are intended to be within the scope of thisinvention. Indeed, various modifications of the invention in addition tothose shown and described herein will become apparent to those skilledin the art from the foregoing description. Such modifications are alsointended to fall within the scope of the appended claims.

1. A compound of the Formula I

wherein A is absent or is selected from

and SO₂; Z is selected from —CH₂, —CH(OH), —CH(C₁-C₆ alkyl), —CH(C₁-C₆alkoxy), —CH(NR⁹R¹⁰), —CH(CH₂(OH)), —CH(CH(C₁-C₄ alkyl)(OH)) and—CH(C(C₁-C₄ alkyl)(C₁-C₄alkyl)(OH)); R¹ is selected from C₁-C₂₀ alkyl,C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, C₁-C₂₀ alkoxy, C₂-C₂₀ alkenoxy, C₁-C₂₀hydroxyalkyl, C₃-C₈ cycloalkyl, benzo(C₃-C₈ cycloalkyl), benzo(C₃-C₈heterocycloalkyl), C₄-C₈ cycloalkenyl, (C₅-C₁₁)bi- or tricycloalkyl,benzo(C₅-C₁₁)bi- or tricycloalkyl, (C₇-C₁₁)bi- or tricycloalkenyl, (3-8membered) heterocycloalkyl, C₆-C₁₄ aryl and (5-14 membered) heteroaryl,wherein each hydrogen atom of said alkyl, alkenyl, alkynyl, alkoxy andalkenoxy is optionally independently replaced with halo, and whereinsaid cycloalkyl, benzo(C₃-C₈ cycloalkyl), cycloalkenyl, (3-8 membered)heterocycloalkyl, C₆-C₁₄ aryl and (5-14 membered) heteroaryl isoptionally independently substituted with from one to four substituentsindependently selected from C₁-C₁₀ alkyl optionally substituted withfrom one to three halo atoms, C₁-C₁₀ alkoxy optionally substituted withfrom one to three halo atoms, C₁-C₁₀ hydroxyalkyl, halo, —OH, —CN,—NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, —C(═O)R¹¹, C₃-C₈ cycloalkyl and (3-8 membered)heterocycloalkyl; R² is selected from H, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₃-C₈ cycloalkyl and C₃-C₈ cycloalkenyl, wherein R² is optionallyindependently substituted with from one to three substituentsindependently selected from C₁-C₄ alkyl optionally substituted with fromone to three halo atoms, C₁-C₄ alkoxy optionally substituted with fromone to three halo atoms, halo and —OH; or R¹ and R² together with the Agroup when present and the nitrogen atom to which R² is attached, or R¹and R² together with the nitrogen atom to which R¹ and R² are attachedwhen A is absent, may optionally form a four to eight membered ring; R³is selected from H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₅-C₆ cycloalkenyl and (3-8 membered) heterocycloalkyl,wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl andheterocycloalkyl are each optionally independently substituted with fromone to three substituents independently selected from C₁-C₄ alkoxy,halo, —OH, —S(C₁-C₄)alkyl —O(C₁-C₄)alkyl and (3-8 membered)heterocycloalkyl; R⁴ is H, C₁-C₆ alkyl or halo; or R³ and R⁴ maytogether with the carbon atom to which they are attached optionally forma moiety selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,morpholino, piperidino, pyrrolidino, tetrahydrofuranyl andperhydro-2H-pyran, wherein said moiety formed by R³ and R⁴ is optionallysubstituted with from one to three substituents independently selectedfrom C₁-C₆ alkyl optionally substituted with from one to three haloatoms, C₁-C₆ alkoxy optionally substituted with from one to three haloatoms, halo, —OH, —CN and allyl; R⁶ is selected from H, C₁-C₆ alkyl,C₂-C₆ alkylene, C₁-C₆ alkoxy, halo, —CN, C₃-C₁₂ cycloalkyl, C₄-C₁₂cycloalkenyl (5-10 membered) heteroaryl and C₆-C₁₀ aryl, wherein saidalkyl, alkylene and alkoxy of R⁶ are each optionally independentlysubstituted with from one to three substituents independently selectedfrom halo and —CN, and wherein said cycloalkyl, cycloalkenyl, heteroaryland aryl of R⁶ are each optionally independently substituted with fromone to three substituents independently selected from C₁-C₄ alkyloptionally substituted with from one to three halo atoms, C₁-C₄ alkoxyoptionally substituted with from one to three halo atoms, halo and —CN;R⁷ is selected from H, C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy, C₁-C₂₀ hydroxyalkyl,C₃-C₁₂ cycloalkyl, C₄-C₁₂ cycloalkenyl, (C₅-C₂₀) bi- or tricycloalkyl,(C₇-C₂₀)bi- or tricycloalkenyl, (3-12 membered) heterocycloalkyl, (7-20membered) heterobi- or heterotricycloalkyl, C₆-C₁₄ aryl and (5-15membered) heteroaryl, wherein R⁷ is optionally independently substitutedwith from one to four substituents independently selected from C₁-C₂₀alkyl optionally substituted with from one to three halo atoms, C₁-C₂₀alkoxy, —OH, —CN, —NO₂, —NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, —C(═O)R¹¹, —C(═O)OR¹¹,—S(O)_(n)NR⁹R¹⁰, —S(O)_(n)R¹¹, C₃-C₁₂ cycloalkyl, (4-12 membered)heterocycloalkyl optionally substituted with from one to three OH orhalo groups, (4-12 membered) heterocycloalkoxy, C₆-C₁₄ aryl, (5-15membered) heteroaryl, C₆-C₁₂ aryloxy and (5-12 membered) heteroaryloxy;or R⁶ and R⁷ may together with the carbon and nitrogen atoms to whichthey are respectively attached optionally form a (5-8 membered)heterocycloalkyl ring, a (5-8 membered) heterocycloalkenyl ring or a(6-8 membered) heteroaryl ring, wherein said heterocycloalkyl,heterocycloalkenyl and heteroaryl rings are each optionallyindependently substituted with from one to three substituentsindependently selected from halo, C₁-C₆ alkyl, optionally subsitutedwith from one to three halo atoms, C₁-C₆ alkoxy optionally subsitutedwith from one to three halo atoms, C₁-C₆ hydroxyalkyl, —OH,(CH₂)_(zero-10)NR⁹R¹⁰, (CH₂)_(zero-10)C(═O)NR⁹R¹⁰, —O₂NR⁹R¹⁰ and C₃-C₁₂cycloalkyl; R⁹ and R¹⁰ are each independently selected from H, C₁-C₁₀alkyl wherein each hydrogen atom of said C₁-C₁₀ alkyl is optionallyindependently replaced with a halo atom, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl,C₁-C₆ alkoxy wherein each hydrogen atom of said C₁-C₆ alkoxy isoptionally independently replaced with a halo atom, C₂-C₆ alkenoxy,C₂-C₆ alkynoxy, —C(═O)R¹¹, —S(O)_(n)R¹¹, C₃-C₈ cycloalkyl, C₄-C₈cycloalkenyl, (C₅-C₁₁)bi- or tricycloalkyl, (Cr C₁₁)bi- ortricycloalkenyl, (3-8 membered) heterocycloalkyl, C₆-C₁₄ aryl and (5-14membered) heteroaryl, wherein said alkyl and alkoxy are each optionallyindependently substituted with from one to three substituentsindependently selected from halo and —OH, and wherein said cycloalkyl,cycloalkenyl, bi- or tricycloalkyl, bi- or tricycloalkenyl,heterocycloalkyl, aryl and heteroaryl are each optionally independentlysubstituted with from one to three substituents independently selectedfrom halo, —OH, C₁-C₆ alkyl optionally independently substituted withfrom one to six halo atoms, C₂-C₆ alkenyl, C₂-C₆ alkenyl, C₁-C₆ alkoxy,C₂-C₆ alkenoxy, C₂-C₆ alkynoxy and C₁-C₆ hydroxyalkyl; or NR⁹R¹⁰ mayform a (4-7 membered) heterocycloalkyl, wherein said heterocycloalkyloptionally comprises from one to two further heteroatoms independentlyselected from N, O and S, and wherein said heterocycloalkyl optionallycontains from one to three double bonds, and wherein saidheterocycloalkyl is optionally independently substituted with from oneto three substituents independently selected from C₁-C₆ alkyl optionallysubstituted with from one to six halo atoms, C₂-C₆ alkenyl, C₂-C₆alkenyl, C₁-C₆ alkoxy, C₂-C₆ alkenoxy, C₂-C₆ alkynoxy, C₁-C₆hydroxyalkyl, C₂-C₆ hydroxyalkenyl, C₂-C₆ hydroxyalkenyl, halo, —OH,—CN, —NO₂, —C(═O)R¹¹, —C(═O)OR¹¹, —S(O)_(n)R¹¹ and —S(O)_(n)NR⁹R¹⁰; R¹¹is selected from H, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₄-C₈ cycloalkenyl,(C₅-C₁₁)bi- or tricycloalkyl, —(C₇-C₁₁)bi- or tricycloalkenyl, (3-8membered) heterocycloalkyl, C₆-C₁₀ aryl and (5-14 membered) heteroaryt,wherein said alkyl of R¹¹ is optionally independently substituted withfrom one to three substituents independently selected from —OH, —CN andC₃-C₈ cycloalkyl, and wherein each hydrogen atom of said alkyl isoptionally independently replaced with a halo atom, and wherein saidcylcoalkyl, cycloalkenyl, heterocycloalkyl, aryl and hetereoaryl of R¹¹are each optionally independently substituted with from one to threesubstituents independently selected from halo, C₁-C₈ alkyl optionallysubstituted with from one to three halo atoms, —OH, —CN and C₃-C₈cycloalkyl; and n is in each instance an integer independently selectedfrom zero, 1, 2 and 3; or a pharmaceutically acceptable salt thereof. 2.A compound according to claim 1, wherein A is absent or is

Z is —CH₂, —CH(OH) or —CH(C₁-C₆ alkyl); R¹ is C₁-C₁₀ alkyl, C₆-C₁₀ aryl,(6-10 membered) heteroaryl or benzo(C₅-C₆ cycloalkyl), wherein when R¹is C₆-C₁₀ aryl, C₆-C₁₀ heteroaryl or benzo(C₅-C₆ cycloalkyl), R¹ isoptionally independently substituted with from one to three substituentsindependently selected from C₁-C₆ alkyl, halo and OH; R² is H or C₁-C₆alkyl; R³ is H, —CH₂CH₂SCH₃—O(C₁-C₄)alkyl or C₁-C₆ alkyl; R⁴ is H orC₁-C₆ alkyl; R⁶ is H or C₁-C₆ alkyl; R⁷ is C₁-C₁₀ alkyl, C₃-C₈cycloalkyl or (4-10 membered) heterocycloalkyl, wherein R⁷ is optionallyindependently substituted with from one to three substituentsindependently selected from C₁-C₈ alkyl, C₁-C₈ alkoxy, OH, —NR⁹R¹⁰,—C(═O)NR⁹R¹⁰, —C(═O)R¹¹, —C(═O)OR¹¹ and (4-6 membered) heterocycloalkyloptionally substituted with from one to three OH or halo groups; and R⁹,R¹⁰ and R¹¹ are each independently selected from H and C₁-C₆ alkyl,wherein each hydrogen atom of said C₁-C₆ alkyl is optionallyindependently replaced with a halo atom.
 3. A compound according toclaim 2, wherein A is absent; R¹ is benzo(C₅-C₆ alkyl) optionallysubstituted with from one to three substituents independently selectedfrom C₁-C₆ alkyl, halo and OH; R² is H or C₁-C₆ alkyl; R³ is H,—CH₂CH₂SCH₃, —CH₂CH₂OCH₃ or C₁-C₆ alkyl; R⁴ is H or C₁-C₆ alkyl; R⁶ is Hor C₁-C₆ alkyl; R⁷ is C₁-C₁₀ alkyl, wherein R⁷ is optionallyindependently substituted with from one to three substituentsindependently selected from C₁-C₈ alkoxy, OH, —NR⁹R¹⁰, —C(═O)NR⁹R¹⁰,—C(═O)R¹¹, —C(═O)OR¹¹ and (4-6 membered) heterocycloalkyl.
 4. A compoundaccording to claim 3, wherein R⁷ is optionally substituted with —NR⁹R¹⁰,morpholino, pyrrolidinyl or piperidinyl.
 5. A compound according toclaim 3, wherein R⁴ is H and R³ is methyl, ethyl butyl, isobutyl,propyl, isopropyl, CH₂CH₂SCH₃ or —CH₂CH₂OCH₃.
 6. A compound according toclaim 3, wherein R¹ is 1, 2, 3, 4-tetrahydronaphthalene or indanyloptionally substituted with 1 to 3 fluorine or chlorine atoms.
 7. Acompound according to claim 2, wherein A is

Z is —CH₂, —CH(OH) or —CH(C₁-C₆ alkyl); R¹ is C₁-C₁₀ alkyl, C₆-C₁₀ arylor (6-10 membered) heteroaryl, wherein said alkyl, aryl and heteroarylare optionally independently substituted with from one to threesubstituents independently selected from C₁-C₆ alkyl, halo and OH; R² isH or C₁-C₆ alkyl; R³ is H or C₁-C₆ alkyl; R⁴ is H or C₁-C₆ alkyl; R⁶ isH or C₁-C₆ alkyl; R⁷ is C₁-C₁₀ alkyl, C₃-C₈ cycloalkyl or (4-10membered) heterocycloalkyl, wherein R⁷ is optionally independentlysubstituted with from one to three substituents independently selectedfrom C₁-C₈ alkyl, C₁-C₈ alkoxy, OH, —NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, —C(═O)R¹¹,—C(═O)OR¹¹ and (4-6 membered) heterocycloalkyl optionally substitutedwith from one to three OH or halo groups.
 8. A compound according toclaim 7, wherein the (4-10 membered) heterocycloalkyl group of R⁷ isazetidinyl, pyrrolidinyl or piperidinyl; and the (4-6 membered)heterocycloalkyl substituent of R⁷ is morpholino, pyrrolidinyl orpiperidinyl.
 9. A compound according to claim 7, wherein R¹ is aryl, Ais

Z is —CH₂.
 10. A compound according to claim 9, wherein and R⁷ is aC₁-C₆ alkyl optionally substituted with —NR9R¹⁰, morpholino,pyrrolidinyl or piperidinyl.
 11. A compound according to claim 1selected from the group consisting of:3-(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-butyricacid methyl ester;3-{4-[2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoylamino]-imidazol-1-yl}-3-methyl-butyricacid methyl ester;3-(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-3-methyl-butyricacid methyl ester;3-{4-[2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoylamino]-imidazol-1-yl}-3-methyl-butyricacid methyl ester; 2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoicacid [1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid[1-(1-ethyl-propyl)-1H-imidazol-amide2-(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-2-methyl-propionicacid methyl ester;2-(4-{2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoylamino}-imidazol-1-yl)-2-methyl-propionicacid methyl ester;2-{4-[2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoylamino]-imidazol-1-yl}-2-methyl-propionicacid methyl ester;2-{4-[2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoylamino]-imidazol-1-yl}-2-methyl-propionicacid methyl ester;3-(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-propionylamino}-imidazol-1-yl)-3-methyl-butyricacid methyl ester;3-{4-[2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-propionylamino]-imidazol-1-yl}-3-methyl-butyricacid methyl ester;4-(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-piperidine-1-carboxylicacid tert-butyl ester; 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoicacid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-[2-(3-Trifluoromethyl-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-[2-(3-Trifluoromethoxy-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid[1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide;2-[2-(4-Phenyl-thiazol-2-yl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-[2-(3-Trifluoromethyl-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid[1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid[1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid[1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-4-methyl-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-propionamide;(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-aceticacid methyl ester;2-(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-2-methyl-imidazol-1-yl)-2-methyl-propionicacid methyl ester; 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoicacid [1-(2-methoxy-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide;4-(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-benzoicacid methyl ester; 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoicacid{1-[1-(2,2-dimethyl-propyl)-pyrrolidin-3-yl]-1H-imidazol-4-yl}-amide;3-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoylamino]-imidazol-1-yl}-butyricacid methyl ester;2-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoylamino]-imidazol-1-yl}-2-methyl-propionicacid methyl ester;2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide;3-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoylamino]-imidazol-1-yl}-3-methyl-butyricacid methyl ester; 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoicacid [1-(2-isopropylamino-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-2-methylamino-ethyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(2-benzylamino-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{1-[2-(2,2-dimethyl-propylamino)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(2-dimethylamino-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{1-[1,1-dimethyl-2-(1-phenyl-ethylamino)-ethyl]-1H-imidazol-4-yl}-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-3-morpholin-4-yl-propyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-3-pyrrolidin-1-yl-propyl)-1H-imidazol-4-yl]-amide;2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(5-Chloro-indan-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(Indan-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(6-Fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(6-Chloro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(6,8-Dichloro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(5,7-Dimethyl-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(1,2,3,4-Tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(6-Isopropyl-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-[2-(2-Fluoro-phenyl)-1-methyl-ethylamino]-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-[1-Methyl-2-(3-trifluoromethyl-phenyl)-ethylamino]-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(6-Bromo-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-ethylamino]-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-1-methyl-ethylamino]-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide;2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-3-morpholin-4-yl-propyl)-1H-imidazol-4-yl]-amide;2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{1-[1,1-dimethyl-2-(1-phenyl-ethylamino)-ethyl]-1H-imidazol-4-yl}-amide;2-(6,8-Dichloro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)₄-methyl-pentanoicacid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-N-[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-propionamide;2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(2-dimethylamino-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide;4-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoylamino]-imidazol-1-yl}-benzoicacid methyl ester;2-(6,8-Difluoro-1,1-dimethyl-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoicacid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(6-Isopropyl-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(2-hydroxy-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(2-hydroxy-ethyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(2-hydroxy-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(3-hydroxy-1,1-dimethyl-propyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(1-piperidin-4-yl-1H-imidazol-4-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1-methyl-piperidin-4-yl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1-acetyl-piperidin-4-yl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(1-piperidin-4-yl-1H-imidazol-4-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{1-[1-(3,3-dimethyl-butyryl)-piperidin-4-yl]-1H-imidazol-4-yl}-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{1-[1-(3,3-dimethyl-butyl)-piperidin-4-yl]-1H-imidazol-4-yl}-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{1-[1-(2,2-dimethyl-propyl)-piperidin-4-yl]-1H-imidazol-4-yl}-amide;2-[6-(4-Fluoro-phenyl)-1,2,3,4-tetrahydro-naphthalen-2-ylamino]-pentanoicacid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-[(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-methyl-amino]-pentanoicacid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[7-(2,2-dimethyl-propyl)-5,5-dimethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-1-yl]-amide;2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid{1-[2-(2,2-dimethyl-propylamino)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-amide;2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-piperidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(2-dimethylamino-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide;2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid{1-[1,1-dimethyl-2-(2,2,2-trifluoro-ethylamino)-ethyl]-1H-imidazol-4-yl}-amide;2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1-(3-hydroxy-cyclobutyl)-1H-imidazol-4-yl]-amide;2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid(1-[2-(2,6-dimethyl-morpholin-4-yl)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-amide;2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid(1-{2-[(2,2-dimethyl-propyl)-methyl-amino]-1,1-dimethyl-ethyl}-1H-imidazol-4-yl)-amide;2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid{1-[1,1-dimethyl-2-(4-methyl-piperazin-1-yl)-ethyl]-1H-imidazol-4-yl}-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{1-[2-(2,2-dimethyl-propylamino)-ethyl]-1H-imidazol-4-yl}-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{1-[2-(4-methyl-piperazin-1-yl)-ethyl]-1H-imidazol-4-yl}-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(2-hydroxy-1,1,2-trimethyl-propyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(3-hydroxy-1,1,3-trimethyl-butyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(2-ethyl-2-hydroxy-1,1-dimethyl-butyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(3-ethyl-3-hydroxy-1,1-dimethyl-pentyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(1-tert-butyl-1H-imidazol-4-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid(1-tert-butyl-1H-imidazol-4-yl)-amide;2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid(1-tert-butyl-1H-imidazol-4-yl)-amide;2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid(1-tert-butyl-1H-imidazol-4-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-N-(1-isopropyl-1H-imidazol-4-yl)-propionamide;2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid(1-isopropyl-1H-imidazol-4-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{1-[2-(3-hydroxy-pyrrolidin-1-yl)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{1-[1-(2,2-dimethyl-propyl)-azetidin-3-yl]-1H-imidazol-4-yl}-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{1-[1-(2,2-dimethyl-propionyl)-azetidin-3-yl]-1H-imidazol-4-yl}-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(2-isopropoxy-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide;2-(6,8-Difluoro-1,2,3,4-tetrahydro-1,4-methano-naphthalen-2-ylamino)-pentanoicacid [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(5,7-Difluoro-chroman-3-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(4,6-Difluoro-tricyclo[6,2,2]dodeca-2(7),3,5-trien-9-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(Naphthalen-2-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(Quinolin-3-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(1-Methyl-1H-indol-3-ylamino)-pentanoic acid[1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-2-trifluoromethyl-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-2-fluoro-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-2-phenyl-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-5-phenyl-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-5-trifluoromethyl-1H-imidazol-4-yl]-amide;5-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-3-(1,1-dimethyl-2-pyrrolid in-1-yl-ethyl)-3H-imidazole-4-carboxylic acid methyl ester;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(6,6-dimethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-1-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(6-methyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(3,4-dihydro-2H-imidazo[5,1-b][1,3]oxazin-8-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(1H-imidazo[1,2-a]pyridin-3-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-ethylamino]-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-ethylamino]-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-1-methyl-ethylamino]-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(3,5-Difluoro-benzylamino)-pentanoic acid[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid[1(1-dimethylaminomethyl-cyclopentyl)-1H-imidazol-4-yl]-amide; and2-(6,8-Difluoro-1-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoicacid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amideand pharmaceutically acceptable salts thereof.
 12. A compound of claim1, wherein the stereochemistry of the R³ and R⁴ substituents are shownbelow:


13. A compound of claim 12, wherein R⁴ and R² are —H.
 14. Apharmaceutical composition for treating a disease or condition selectedfrom the group consisting of Alzheimer's disease, hereditary cerebralhemorrhage with amyloidosis, cerebral amyloid angiopathy, aprion-mediated disease, inclusion body myositis, stroke, multiplesclerosis, head trauma, mild cognitive impairment and Down's Syndrome ina mammal, comprising an amount of the compound according to claim 1 thatis effective in inhibiting Ap-peptide production or treating suchdisease or condition, and a pharmaceutically acceptable carrier.
 15. Amethod of inhibiting Aβ-peptide production in a mammal, comprisingadministering to said mammal an amount of the compound according toclaim 1 that is effective in inhibiting Aβ-production.
 16. A method oftreating a disease or condition selected from the group consisting ofAlzheimer's disease, hereditary cerebral hemorrhage with amyloidosis,cerebral amyloid angiopathy, a prion-mediated disease, inclusion bodymyositis, stroke, multiple sclerosis, head trauma, mild cognitiveimpairment and Down's Syndrome in a mammal, comprising administering tosaid mammal an amount of the compound according to claim 1 that iseffective in inhibiting Aβ-production or treating such disease orcondition.
 17. A method of treating a disease or condition associatedwith Aβ-peptide production in a mammal, comprising administering to saidmammal (a) the compound according to claim 1; and (b) a memoryenhancement agent, antidepressant, anxiolytic, antipsychotic agent,sleep disorder agent, anti-inflammatory agent, anti-oxidant agent,cholesterol modulating agent, a Histamine (H2) antagonist oranti-hypertensive agent; wherein the active agents “a” and “b” above arepresent in amounts that render the composition effective in treatingsuch disease or condition.
 18. A method of treating a disease orcondition selected from the group consisting of Alzheimer's disease,hereditary cerebral hemorrhage with amyloidosis, cerebral amyloidangiopathy, a prion-mediated disease, inclusion body myositis, stroke,multiple sclerosis, head trauma, mild cognitive impairment and Down'sSyndrome, in a mammal, comprising administering to said mammal (a) thecompound according to claim 1; and (b) a memory enhancement agent,antidepressant, anxiolytic, antipsychotic agent, sleep disorder agent,anti-inflammatory agent, anti-oxidant agent, cholesterol modulatingagent, a Histamine (H2) antagonist or anti-hypertensive agent; whereinthe active agents “a” and “b” above are present in amounts that renderthe composition effective in treating such disease or condition.
 19. Apharmaceutical composition for treating a disease or conditionassociated with the modulation of the Notch signaling pathway comprisingthe compound of Formula I according to claim 1, or theirpharmaceutically acceptable salts.
 20. The composition of claim 19,wherein the disease or condition is selected from the group consistingof cancer, arteriosclerosis, diabetic retinopathy, rheumatoid arthritis,psoriasis, inflammatory bowel disease, inflammation, asthma, graftrejection, graft versus host disease, autoimmune disease and transplantrejection.
 21. The composition of claim 20, wherein the disease orcondition is selected from the group consisting of cancer.
 22. A methodof treating a disease or condition selected from the group consisting ofcancer, arteriosclerosis, diabetic retinopathy, rheumatoid arthritis,psoriasis, inflammatory bowel disease, inflammation, asthma, graftrejection, graft versus host disease, autoimmune disease and transplantrejection, comprising administering to said mammal an amount of thecompound according to claim 1 that is effective in modulating Notchsignaling pathway or treating such disease or condition.